Nitrogen heterocycles for therapeutic administration

ABSTRACT

SUBSTITUTED 6,7-DIALKOXYQUINAZOLINES, 4-(6,7-DIALKOXYQUINOLIN-4-YL)-PIPERAZINE-1 - CARBOXYLIC ACID, ESTERS AND 1-AMINO-6,7-DIALKOXYISOQUINOLINES AND THEIR PHARMACEUTICALLY-ACCEPTABLE ACID ADDITION SALTS. COMPOUNDS MANIFEST BRONCHODILATOR ACTIVITY AND ANTIHYPERTENSIVE RESPONSE WITH MINIMAL ADVERSE EFFECTS UPON ADMINISTRATION TO AFFLICTED SUBJECTS.

United States Patent O1 Tree 3,594,480 NITROGEN HETEROCYCLES FORTHERAPEUTIC ADMINISTRATION Timothy H. Cronin, Niantic, and Hans-JurgenE. Hess, Old Lyme, Conm, assignors to Pfizer Inc., New York,

No Drawing. Application Oct. 26, 1967, Ser. No. 678,191,

now Patent No. 3,517,005, which is a continuation-inpart of applicationSer. No. 590,494, Oct. 31, 1966. Divided and this application Mar. 12,1970, Ser. No.

Int. Cl. A61k 27/00 US. Cl. 424-250 23 Claims ABSTRACT OF THE DISCLOSURECROSS REFERENCE TO RELATED APPLICATIONS This application is a divisionof application Ser. No. 678,191, filed Oct. 26, 1967, now US. Patent3,517,005 which, in turn, is a continuation-in-part of application Ser.No. 590,494, filed Oct. 31, 1966 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to certain novelorganic nitrogen compounds, and more particularly, it is concerned withvarious new and useful organic heterocyclic nitrogen compounds which arevaluable in alleviating bronchoconstriction in afllicted subjects and inreducing the blood pressure of hypertensive subjects.

Treatment subjects suffering from bronchoconstriction or hypertensionrequires that the therapeutic agent eifectively cause bronchodilation orlower the blood pressure of the treated subject at dosage levels whichdo not cause other undesirable effects in the subject. The compounds ofthis invention manifest bronchodilatory and/ or hypotensive activity atdosage levels at which no adverse effects are manifested in the treatedindividual.

SUMMARY OF THE INVENTION The compounds of this invention are those ofthe following formulae:

and

3,594,480 Patented July 20, 1971 and their pharmaceutically-acceptableacid addition salts.

In these compounds A and B may each be alkoxy containing from 1 to 5carbon atoms, hydrogen, hydroxy, or methyl. When A or B are hydrogen,the other is never hydrogen and A and B, taken together, may be benzo oralkylenedioxy having up to 4 carbon atoms. R may be H or alkylcontaining from 1 to 6 carbon atoms. R and R may each be H, phenyl,phenylalkyl, alkyl, alkenyl, hydroxyalkyl or cycloalkyl, the alkyl,alkenyl and cycloalky moieties having up to 6 carbon atoms. Z is CH 0 orN, provided that when Z is CH or O, n is equal to one and when Z is N, nis equal to one or two. R may be H, alkyl, 'alkenyl, aryl hydrocarbon,alkylcarbonyl, aryloxycarbonyl, alkenyloxycarbonyl, benzoyl naphthoyl oralkyloxycarbonyl, the alkyl and alkenyl moieties having up to 6 carbonatoms and the aryl hydrocarbon moiety having up to 10 carbon atoms. R RR and R may each be H, alkyl containing from 1 to 4 carbon atoms orhydroxymethyl. R and R taken together, may be cycloalkyl having from 4to 7 carbon atoms. I may be H, hydroxy, formyloxy, acyloxy containingfrom 2 to 5 carbon atoms, aroyloxy containing up to 11 carbon atoms,alkoxy containing from 1 to 4 carbon atoms, aryloxy containing up to 10carbon atoms, chloro, bromo formamido, alkylamido having up to 4 carbonatoms in the alkyl group, arylamido having up to 10 carbon atoms in thearyl group, or amino, containing up to two substituents. Each aminosubstituent may be hydrogen, alkyl having up to 4 carbon atoms or arylcontaining up to 10 carbon atoms, and the two substituents, taken together, may be cycloalkyl containing from 4 to 7 carbon atoms and p maybe one or two.

These compounds are useful as bronchodilators and as anti-hypertensiveagents and are also useful in other manners.

The compounds which are particularly useful in effecting hypotensiveaction are those numbered I and III while compounds of all the depictedformulae exhibit useful broncholidator activity. Compounds which arepreferred as bronchodilators are the disclosed6,7-dimethoxyquinazolines, the 6,7-ethylene dioxyquinazolines the6,7-diiso-propoxyquinazolines as well as the 7-methoxyquinazolines. Ofparticular interest as bronchodilators are the compound 4-amino-6,7dimethoxyquinazoline, the compound 2-ethyl-4-amino 6,7dimethoxyquinazoline, the compound 4-(6,7dimethoxyquinazolint-yl)-piperazine- 1 carboxylic acid, isobutyl ester,the compound 4-(2-npropyl-6,7-dimethoxyquinazolin-4-yl)-piperazine 1carboxylic acid, isobutyl ester, the compound 4-(2-methyl-6,7-dimethoxyquinazolin-4-yl) piperazine l-carboxylic acid, isobutylester the compound 4(2-ethyl-6,7-dimethoxyquinazolin-4-yl) piperazinel-carboxylic acid, isobutyl ester, the compound4-(6,7-dimethoxyquinazolin-4- yl)-piperazine-1-carboxylic acid, 2 methyl2-hydroxypropyl ester, the compound 4-(6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid, 2-methyl-2-chloropropy1 ester, and thecompound 4-( 6,7 dimethoxyquinazolin-4- piperazine-1-carboxylic acid, 2methyl 2-chloropropyl ester.

These compounds are also useful in effecting smooth muscle relaxation insubjects to which the compounds are administered.

Of particular interest as hypotensive agents are the compound2-ethyl-4-amino-6,7-dimethoxyquinazoline, the compound2-methyl-4-amino-6,7-dimethoxy quinazoline, the compound4-amino-6,7-dimethoxyquinazoline, and the compound2-n-propyl-4-amino-6,7-dimethoxyquinazoline.

Other compounds of this invention are those of the formula:

N A- R1 [N N c 1 1 I h VI and their pharmaceutically-acceptable acidaddition salts.

In these compounds of Formula VI, A and B may each be alkoxy containingfrom 1 to 5 carbon atoms, hydrogen, hydroxy, or methyl. When A or B arehydrogen, the other is never hydrogen. A and B, taken together, may bebenzo or alkylenedioxy having up to 4 carbon atoms. R may be H or alkylcontaining from 1 to 6 carbon atoms. R R R and R each may be H, alkylcontaining from 1 to 4 carbon atoms or hydroxymethyl and R and R takentogether, may be cycloalkyl having from 4 to 7 carbon atoms. I may be H,hydroxy, formyloxy, acyloxy containing from 2 to 5 carbon atoms,aroyloxy containing up to 11 carbon atoms, alkoxy containing from 1 to 4carbon atoms, aryloxy containing up to 10 carbon atoms, chloro, bromo,formamido, alkylamido having up to 4 carbon atoms in the alkyl group,arylamido having up to 10 carbon atoms in the aryl group, or amino,containing up to two substituents. Each amino substituent may behydrogen, alkyl having up to 4 carbon atoms or aryl containing up to 10carbon atoms. The two substituents, taken together, may be cycloalkylcontaining from 4 to 7 carbon atoms.

These compounds are useful as bronchodilators and as smooth musclerelaxants. Of particular interest as bronchodilators are the compound4-(6,7-dimethoxyquinolin-4- yl)-piperazine-l-carboxylic acid, isobutylester, and the 4 compound 4-(6,7-dimethoxyquinolin-4-yl) piperazine-1-carboxylic acid, 2-methyl-2-hydroxypropy1 ester.

Other compounds of this invention are those of the formulae:

V II

and

G VIII and and their pharmaceutically-acceptable acid addition salts.

In the compounds of Formulae VII, VIII and IX, A and B may each bealkoxy containing from 1 to 5 carbon atoms, hydrogen, hydroxy, ormethyl. When .A or B are hydrogen, the other is never hydrogen. A and B,taken together may be benzo or alkylenedioxy having up to 4 carbonatoms. R is H or alkyl containing from 1 to 6 carbon atoms. R and R mayeach be H, alkyl or alkenyl containing up to 6 carbon atoms, arylhydrocarbon containing up to 10 carbon atoms, aralkyl hydrocarboncontaining up to 3 carbon atoms in the alkyl moiety and 7 carbon atomsin the aryl moiety, or fl-hydroxyethyl. When R and R are aryl oraralkyl, the aryl moiety may be substituted with up to 3 substituentswhich may be halogen or alkoxy containing up to 4 carbon atoms. R and Rtaken together, may be cycloalkyl containing from 3 to 7 carbon atoms.

G may be oxygen, sulfur, amino, alkylamino having up to 6 carbon atomsin the alkyl group, alkenylamino having from 3 to 6 carbon atoms in thealkenyl moiety, unsubstituted aryl hydrocarbon amino having up to 10carbon atoms in the aryl moiety, acylamino having up to 6 carbon atomsin the acyl moiety, aroylamino having up to 11 carbon atoms in the aroylmoiety, carbalkoxyamino having up to 6 carbon atoms in the alkyl moiety,carbalkenyloxyamino having up to 6 carbon atoms in the alkenyl moiety orcarbaryloxyamino having up to 10 carbon atoms in the aryl moiety. R R Rand R may each be H, alkyl containing from 1 to 4 carbon atoms orhydroxymethyl. R and R taken together, may be cycloalkyl having from 4to 7 carbon atoms.

3' may be H, hydroXy, formyloxy, acyloxy containing from 2 to 5 carbonatoms, aroyloxy containing up to 11 carbon atoms, alkoxy containing from1 to 4 carbon atoms, aryloxy containing up to 10 carbon atoms, chloro,bromo, formamido, alkylamino having up to 4 carbon atoms in the alkylgroup, arylamido having up to 10 carbon atoms in the aryl group oramino, containing up to two substituents. Each amino substituent may behydrogen, alkyl having up to 4 carbon atoms or aryl containing up tocarbon atoms. The two substituents, taken together, may be cycloalkylcontaining from 4 to 7 carbon atoms.

These compounds of Formulae VII, VIII and IX are useful asbronchodilators and as smooth muscle relaxants. Particularly preferredas bronchodilators are the compound 4-(6,7-dimethoxyisoquinolin-l-yl)piperazine-lcarboxylic acid, isobutyl ester, the compound 4-(6,7-dimethoxyisoquinolin-1-yl) piperazine-l-carboxylic acid, ethyl ester,the compound 4-(6,7-dimethoxy-isoquinolin-1- yl)-piperazine 1 carboxylicacid, 2-methyl-2-hydroxypropyl ester, and the compound4-ethylamino-6,7-dimethoxyisoquinoline.

DETAILED DESCRIPTION OF THE INVENTION This invention concerns thecompounds of Formulae I, II, III, IV, V, VA, VI, VII, VIII and XI.

Compounds I, II and V may be prepared from the appropriate substitutedo-aminobenzoic acid amides. The amides are reacted with appropriatealkanoyl chlorides to form substituted o-alkanamido benzoic acid amideswhich are then cyclized in alkaline ethanol to2-alkyl-6,7-dialkoXy4(3H)-quinazolinone. Where the '2-substituent is tobe hydrogen, the substituted o-aminobenzoic acid amide may be cyclizedby reacting it with formic acid. The 2- substituent on the resultantquinazoline is controlled by the nature of the alkanoyl chloride whichis used. The 6- and 7-substituents on the resultant quinazoline aredetermined by the nature of the substituents on the original substitutedo-aminobenzoic acid amide. The resultant quinazolinone is chlorinated to2-alkyl-4-chloro-6,7-dialkoxyquinazoline using phosphorous oxychloride.

The 2-alkyl-4-chloro-6,7-dialkoxyquinazoline is aminated to the desired2-alkyl-4-imino-6,7-dialkoxyquinazoline by reacting it with theappropriate amine or ammonia. The structure of the 4-substituent on thequinazoline is determined by the structure of the amine with which the4-chloroquinaz0line is reacted. The amination generally is carried outin an aqueous or organic solvent and, while ethanol is a preferredsolvent, other polar solvents such as dimethylformamide, dioxane,tetrahydrofuran or methanol may be used. A molar excess of amine isgenerally employed. The reaction mixture is heated from to 150 C. andfrom 1 to 13 hours under reflux conditions or in a pressure vessel.Preferred reaction times and temperatures are from 75 to C. and from 2.5to 3.5 hours for alkylamino or heterocyclic amino substituents and fromto C. and from 11 to 13 hours where ammonia in ethanol is used.

The reaction sequences are shown for4-(6,7-dimethoxyquinazoline-4-yl)-piperazine-1-carboxylic acid, isobutylester and for 2propyl-4-amino-6,7-dimethoxyquinazoline.

The reaction sequence for 2-propyl-4-amino-6,7-dimethoxyquinazoline isas follows:

0 ll C330 NHZ 031170 or CH30 coNn, Pyndine t i CH3O N O CH7 1. equiv.KOH 011.0- OONH2 EtOH N CH30- j-C3H7 P0013 CH30- N N 01130 I e rnNEE/Eton 01130 03111 O CH3O N 130440 c. CH3O N I or NH The substituentsat the 6,7-position of the resulting quinazoline are controlled by thesubstituents on the original o-amino benzoic acid amide. Typicalquinazolines, substituted at the 6- or 7-positi0ns or both which areobtainable from substituted o-aminobenzoic acid amides by thecyclization procedure outlined herein are shown in Table I with theirstarting compounds.

Table I.--Substituted Quinazolines Starting Compound: Substituents4-methoxyanthranilamide 7-methoxy-. S-methoxyanthranilamide 6-methoxy-.6-aminoveratramide 6,7dirnethoXy-. 4-ethoxyanthranilamide 7-ethoxy-.4,5-di-n-propyloxyanthranilamide 6,7-di-n-propyloxy.

The 2-alkyl-4-amino-6,7-substituted quinazolines of Formulae I, II and Vmay also be prepared by use of the appropriate2-alkyl-4-bromo-quinazolines, the appropriate2-alkyl-4-alkoxy-quinazolines and the appropriate Z-alkyl-4-thioalkoxy-quinazolines in place of the 2-alkyl-4-chloroquinazolinesused in the procedures outlined above. When these compounds are used inplace of the 4-chloro compounds, the reaction times and reactionconditions may differ from those given for the 4-chloro compounds. Thoseskilled in the art will easily be able to determine the appropriatereaction conditions where the 4-bromo, 4-alkoxy or 4-thioalkoxycompounds are used. The preferred reactants are the 4-bromo or 4-chloroquinazolines.

Compounds III, IV and VA can be prepared from 2,4-dichloro-6,7-dialkoxy-quinazolines. These are prepared by the proceduregiven by F. H. S. Curd et al., J. Chem. Soc. (London), 1759 (1948).Where the Z-amino group is unsubstituted, (R R are hydrogen) analternative method of preparation for compound III may be used whichinvolves the cyclization of the substituted 2-acylanilines withcyanamide.

Where compounds III, IV and VA are to be prepared from2,4-dichloro-6,7-dialkoxyquinazolines, the 4-chloro substituent isreplaced by a diester moiety which is decarboxylated to the desiredalkyl substituent at the 4-position. The nature of the 4-alkylsubstituent is controlled by the ester which is used to replace the4-chloro group. The replacement reaction, which utilizes the appropriatediethyl u-alkylmalonate, is accomplished in a solution of sodium hydridedissolved in dimethylformamide. Diethyl u-alkyl sodium malonate isformed and reacts at the 4-position to replace the 4-chloro substituenton the quinazoline. The reaction may be carried out at temperatures from40 to 100 C. and over a period from about 1 to about 60 hours. Apreferred temperature range is from 50 to 70 C. and a preferred range ofreaction duration is from 35 to 45 hours at these temperatures. Yieldsof desired product range from 40 to 80 percent and 60 percent istypical. The diethyl 4-(2-chloro-6,7-dialkoxyquinazoline)-a-alkylmalonate is decarboxylated to 2- chloro-4-alkyl-6,7-dialkoxyquinazolineusing sodium hydroxide or another suitable alkaline agent.

The 2-chloro position is aminated using ammonia or the appropriate aminedissolved in ethanol or another solvent. Suitable solvents includedimethylformamide, tetrahydrofuran and methanol. Where ethanol is usedthe reaction temperature may be from 100 to 150 C. and 125135 C. is apreferred temperature range. Typical yields are from 40 to 60 percent.The structure of the 2-amino substituent is completely determined by thenature of the amine which is used.

Compounds III, IV and VA may also be prepared from the appropriate2,4-dibromo-6,7-substituted quinazolines, the appropriate2,4-dialkoxy-quinazolines and the appropriate2,4-dithioalkoxy-quinazolines. When these compounds are used in place ofthe 2,4-dichloro-quinazolines, the reaction times and reactionconditions may differ from those given for the 2,4- dichlorocompounds.Those skilled in the art will easily be able to determine theappropriate reaction conditions where the 2,4-dibromo, the 2,4-dialkoxyor the 2,4-dithioalkoxy quinazolines are used in place of the2,4-dichloro quinazolines. The use of the 2,4-dichloro quinazolines isthe preferred synthesis route.

The hydrochloride salt of the resultant 2-amino-4-alkyl-6,7-dialkoxy-quinazoline may be prepared by dissolving the quinazolinein ethanol or a mixture or ethanol and ethyl ether and passing hydrogenchloride gas through the solution for a sufficient period. Thehydrochloride salt is thus formed.

Where Compound III is to be prepared from the appropriateZ-acylanilines, the 2-substituent on the resulting quinazoline is amino.The 2-acylaniline is reacted with cyanamide at a temperature of 50 to 75C. for a period of from 0.5 to 2 hours. A preferable temperature rangeis 50 to 60 C. and a preferable reaction duration, over this temperaturerange, is 30 to 60 minutes.

The compounds of Formula VI are prepared from the corresponding4-chloro-6,7-substituted quinolines. These latter compounds are preparedby the method given by B. Riegel et al., I. Am. Chem. Soc., 68, 1264(1946). The nature of the 6 -and 7-substituents is determined by theoriginal 3,4-disubstituted aniline which is used to prepare the6,7-substituted quinoline. The nature of the 2-substituent is determinedby the malonic ester which is used to cyclize the 3,4-disubstitutedaniline.

The compounds of Formula VI are prepared by reacting the4-chloro-6,7-substituted quinoline with an appropriatepiperazine-l-carboxylic acid ester. This reaction may be carried out inan appropriate aqueous or organic solvent and, while ethanol is apreferred solvent, other polar solvents such as dimethylformamide,dioxane, tetrahydrofuran or methanol may be used. A molar excess of thepiperazine acid ester may be employed. The reaction mixture is heated ata temperature from 100 C. to 170 C. for a period ranging from one tosixteen hours. Preferred reaction times are from 1.5 to 2.5 hours andpreferred temperatures range from 120 C. to 140 C., where ethanol is thesolvent.

An alternative procedure may be used which involves the preparation of4-piperazinyl quinoline, as an intermediate. The compounds of Formula VIare prepared from the intermediate, as indicated below.

The appropriate 4-bromo quinolines, 4-alkoxy quinolines and 4-thioalkoxyquinolines may be used in place of the 4-chloro quinolines to preparethe compounds of Formula VI. When these compounds are used, the reactionduration and conditions may slightly diifer from those used when the4-chloro quinolines are the starting compounds. Those skilled in the artwill easily be able to determine the appropriate reaction conditions foruse where the 4-bromo, 4-alkoxy or 4-thioalkoxy quinolines are used asreactants. The preferred reactants are the 4-chloro quinolines.

Compounds VII, VIII and IX may be prepared from the appropriate 1 chloro6,7 substituted isoquinolines. These latter compounds may be prepared bya method derived from that given by E. L. Anderson et al., J. Am. Pharm.Assoc., Sci. Ed., 41, 643 (1952).

The preparation method involves the reaction of a substitutedphenethylamine with ethyl chloroformate, in benzene, to form thesubstituted phenethyl carbarnic acid, ethyl ester. This latter compoundis cyclized by treatment with polyphosphoric acid at about 140 C. for 30minutes to form the 3,4-dihydro-1(2H)-isoquinolinone which is convertedto the 1(2H)-isoquinolinone by use of a palladium on carbon catalyst.This reaction is continued until hydrogen evolution ceases. Thel(2H)-isoquino linone is converted to the l-chloro-isoquinoline byreaction with phosphorus oxychloride. The l-chloro-isoquinoline isreacted with the appropriate amine to form the compounds of FormulaeVII, VIII, and IX.

A typical reaction scheme may be shown as:

l r A- CH CHNHr Gloom benzene it A CHQCHNHC 02E: polyphosphoric acid140C. B 30 minutes A R1 Pd/C PO01; NH 240C. NH reflux lhour ll I! O O iH A EtOH/130C./16-24 hrs.

As is apparent from the reaction scheme set out above, the substituentsat the 3-, 6- and 7-positions (R A and B) are determined by the natureof the original substituted phenethylamine and the amino substituent atthe 1- position is determined by the amine used in the final reactionstep. In the compounds of Formula IX, where the substituents R R R R andJ are complex, it may be necessary or preferable to form the finalcompound in two or more steps, from the l-chloro compounds, as isoutlined below.

The amination of the l-chloro isoquinoline is generally carried out inan aqueous or organic solvent and, while ethanol is preferred as asolvent, other polar solvents such as dimethylformamide, dioxane,tetrahydrofuran or methanol may be used. A molar excess of amine or basemay be used advantageously. The amination reaction takes place at atemperature ranging from C. to 200 C. and a reaction duration of 10 to36 hours. Preferred reaction temperatures are C. to C. and preferredreaction times range from 16 to 24 hours when ethanol is used as asolvent.

The compounds of Formulae VII, VIII and IX may also be produced usingthe appropriate l-bromo isoquinoline, the l-alkoxy isoquinoline or thel-thioalkoxy isoquinoline in place of the preferred l-chloro compound.Where these compounds are used in place of the l-chloro isoquinolines,the reaction conditions may ditfer from those given above for thel-chloro compound. Those skilled in the art will easily be able todetermine appropriate reaction temperatures and durations for producingthe compounds of Formulae VII, VIII and IX from the l-bromo, l-alkoxy orl-thioalkoxy isoquinolines,

The methods used to prepare the compounds of Formulae VII, VIII and IXmay also be used to prepare compounds of the following Formula X:

where A, B and R are as defined for the .compounds of Formulae VII, VIIIand IX and R R and R are each H v or alkyl having up to 6 carbon atoms.The number of methylene groups, m, is from 2 to 5. These compounds areuseful as intermediates in preparing the compounds of Formulae VII, VIIIand IX.

Where compounds of Formulae II, IV, V, VA, VI and IX are produced it isoften preferable to prepare the final compound from the chloroderivativein two or more steps.

Nevertheless, the final compound may, in some cases, be more easilyprepared in a single step by direct amination of the chloro derivative.Thus, the 4-(2-alkyl-6,7-dimethoXyquinazolin-4-yl)-piperazine 1carboxylic acid, isobutyl esters are prepared, directly, by reacting the2-alkyl-4-chloro-6,7-dimethoxyquinazolines with piperazine-l-carboxylicacid, isobutyl ester. Similarly, the 4-6,7-dimethoXyquinolin-4-y1)-piperazine 1 carboxylic acid, isobutyl esteris prepared, directly, by reacting 4- chloro-6,7-dimethoxyquinoline withthe appropriate ester.

Suitable amino compounds, useful for producing the compounds of thisinvention, in one or more steps, from the chloro derivatives may beprepared by the following scheme:

In these reactions X is chloro or bromo. The last compound is reacteddirectly with the 4-chloro quinazoline, the 4chloro-quinoline or thel-chloro-isoquinoline to form the compounds of this invention where J ischloro or bromo. I

The compound where I is chloro or bromo may then be converted to thecorresponding compound, where J is hydroxyl, by treatment with 0.1 Nhydrochloric acid. The compound where J is hydroxyl may then beconverted to the compounds where J is acyloxy or aroyloxy by use of theappropriate acid chloride.

10 The compounds of Formulae II, IV, V, VA, VI, and IX may also beprepared in several stages, analogously to the scheme shown below:

Compounds where J is alkylamido, arylamido or formamido may be producedfrom compounds where I is unsubstituted amino by treatment of the lattercompounds with the appropriate acid chloride.

Variations of these procedures which also may be used to prepare thecompounds of this invention from other similar compounds and by othermethods will be obvious to those skilled in the art.

The well-known procedures for preparing salts of basic compounds arealso applicable to the preparation of the compounds of this inventionand are illustrated in the eX- amples below. Such salts may be formedwith both pharmaceutically-acceptable and pharmaceutically-unacceptableacids. By "pharmaceutically-acceptable" is meant those salt-formingacids which do not substantially increase the toxicity of the basiccompound. The preferred salts, which are of particular value in therapy,are the acid addition salts. These include salts of mineral acids suchas hydrochloric, hydriodic, hydrobromic, phosphoric, metaphosphoric, andsulfuric acids, as well as salts of organic acids such as tartaric,acetic, citric, malic, maleic, methanesulfonic, ethansulfonic,benzenesulfonic, para-toluenesulfonic and gluconic as well as othersuitable acids.

The pharmaceutically-unacceptable acid addition salts, while not usefulfor therapy, are valuable for use in the isolation and purification ofthese newly discovered compounds. Furthermore, they are useful for thepreparation of the therapeutically valuable pharmaceutically-acceptablesalts. Of this group, the more common salts include those formed withhydrofluoric and perchloric acids. Hydrofluoride salts are particularlyuseful for the preparation of the pharmaceutically-acceptable salts.

The compounds of this invention may be administered to hypertensivesubjects or subjects sufiering from bronchoconstriction in order toalleviate these conditions. The bronchoconstriction may be functional ormay be caused by allergenic conditions or asthmatic conditions or mayhave come about as the result of a microbial infection. The compounds ofthis invention may be administered alone or in combinations withpharmaceutically-acceptable carriers. The proportion of the activeingredient to carrier is determined by the solubility and chemicalnature of the therapeutic compounds, the chosen route of administrationand the needs of the standard pharmaceutical practice. For example,where these compounds are administered in tablet form, excipients suchas lactose, sodium citrate, calcium carbonate and dicalcium phosphatemay be used. Various disintegrants such as starch, alginic acids, andcertain complex silicates, together with lubricating agents such asmagnesium stearate, sodium lauryl sulphate and talc, may

1 1 also be used in producing tablets for the oral administration ofthese compounds. For oral administration in capsule form, lactose andhigh molecular weight polyethylene glycols are preferred materials foruse as pharmaceutically-acceptable carriers. Where aqueous suspensionsare to be used for oral administration, the compounds of this inventionmay be combined with emulsifying or suspending agents. Diluents such asethanol, propylene glycol, glycerine and their combinations may beemployed as well as other materials. Solutions of the compounds of thisinvention in combination with other solutes such as glucose or salinemay be used where the compounds are to be administered parenterally.Such aqueous solutions should be suitably buffered, if necessary, torender them isotonic.

The compounds of this invention may be administered to subjectssuffering from bronchoconstriction by means of inhalators or otherdevices which permit the active compounds to come into direct contactwith the constricted areas of the tissues of the subject.

The dosage required to reduce the blood pressure of hypertensivesubjects and to relieve the bronchoconstriction in affected subjectswill be determined by the nature and the extent of the hypertension orbronchoconstriction. Generally, small dosages will be administeredinitially with gradual increase in dosage until the optimal dosage levelis determined for the particular subject under treatment. It willgenerally be found that when the composition is administered orally,larger quantities of the active ingredient will be required in order toproduce the same level of blood pressure reduction orbronchoconstruction relief as would be produced by the smaller quantityof active compound which is administered parenterally. In general,dosages will be in the range from about 0.02 to 200 milligrams of activeingredient per kilogram of body weight of subject, administered insingle or multiple dosage units. Dosages at this level will effectivelyreduce blood pressure in hypertensive subjects and relievebronchoconstriction in subjects suffering therefrom. Tablets containing0.1 to 50 milligrams of active ingredient are found to be particularlyuseful.

The therapeutic effects of the compounds of this invention have beenevaluated in guinea pigs and dogs. It was found that the compoundsmanifested therapeutic action over extended periods of time, were easilyabsorbed into the treated subjects upon administration and showedrelatively small effects on the central nervous systems of the treatedsubjects. Interestingly, the compound4-(6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid, 2-methyl-Z-hydroxypropyl ester is found in the urine of dogs to which thecompound 4-(6,7-dimethoxyquinazolin-4-yl)- piperazine-l-carboxylic acid,isobutyl ester has been administered. The former compound, wherein J ishydroxy, appears to be a metabolite of the latter compound, where J ishydrogen. The effectiveness of the compounds of this invention astherapeutic agents was measured with respect to theophylline, a knownbronchodilator and with respect to known hypotensive agents.

The compounds of this invention also have been observed to inhibit theactivity of the enzyme phosphodiesterase, which catalyzes the conversionof adenosine- 3',5-monophosphate (3,5-AMP) to adenosine-5'-monophosphate(5-AMP). Thus, in systems containing phosphodiesterase in which it isdesirable to maintain a high 3,5'-AMP level, the instant compounds mightbe used to great advantage. The ability of the novel compounds toinhibit the enzyme activity is of significance since it is well knownthat the mononucleotide 3,5-AMP is an important regular of numerouscellular and tissue processes, e.g. smooth muscle relaxation, lipolysisand glycolysis. The instant compounds are tissue-specific inhibitors ofthe enzyme, i.e., they will inhibit the enzyme in certain tissues andnot in others; therefore, when it is desirable to raise the 3,5-AMPlevel in only one of several types of tissues which are present, use ofthe instant compounds is particularly advantageous.

This phosphodiesterase inhibition is also significant for the relaxationof bronchial and peripheral vascular smooth muscle. Many of the novelcompounds have been evaluated with respect to their ability to inhibitphosphodiesterase activity with a view to their potential activity asbronchodilators, smooth muscle relaxants or antihypertensives.

It will be understood that various changes in the details, materials andsteps which have been herein described and illustrated in order toexplain the nature of this invention may be made by those skilled in theart within the principal scope of the invention.

The following examples are given by way of illustration only and are notto be construed as limiting the scope of this invention in any way.

Example I.-Preparation of4-(2-ethyl-6,7-dimeth0xyquinazoline-4-yl)-piperazine-1-carboxylic acid,isobutyl ester Part A: Preparation of N-carbethoxy-6-aminoveratricacid.A quantity of ethyl chloroformate totaling 20.0 grams (0.185 mole)was added, dropwise, to a solution of 35.0 grams (0.177 mole) of6-aminoveratric acid dissolved in ml. of pyridine. The addition wasaccomplished over a 30 minute period and the temperature of the reactingmixture was always held below 60 C. The precipitation of the productbegan after about half of the dropwise addition had taken place. Aftercompletion of the addition, the mixture was cooled to room temperatureand poured into 400 ml. of water. This mixture was filtered, washed withthree 200 ml. portions of water, and dried over phosphorus pentoxide.The procedure yielded 46.0 grams of N-carbethoxy-6-aminoveratric acid asa white solid with a melting point of 2112l3 C. The procedure produced ayield of 96.5 percent.

Part B: Preparation of 6-aminoveratramide.A slurry of 46.0 grams (0.171mole) of N-carbethoxy-6-aminoveratric acid in 100 ml. of thionylchloride was stirred until the exothermic reaction had subsided. Themixture was then heated for 15 minutes at reflux. The slurry was dilutedwith hexane and refluxed for 15 minutes after which the resultantmixture was filtered to yield 45.0 grams of crude4,5-dimethoxy-N-carboxyanthranilic anhydride. The crude product of thisstep evidenced a melting point of 225256 C. and was used, withoutpurification, as follows.

A slurry of 35.0 grams of the crude 4,5-dimethoxy-N- carboxyanthranilicanhydride with 600 ml. of ethanol saturated with ammonia was stirred atreflux for 30 minutes while a stream of ammonia was passed through themixture. A complete solution resulted after 15 minutes. The solution wascooled to room temperature and filtered and the filtrate wasconcentrated to separate 25.4 grams of crystalline 6-aminoveratramide.This sample evidenced a melting point of 133136 C. Furthercrystallization of the product from benzene yielded an analytical samplewhich evidenced a melting point of 147148 C.

Analysis.Calcd for C H H O (percent): C, 55.09; H, 6.17; N, 14.28. Found(percent): C, 55.24; H, 5.83; N, 14.54.

Part C: Preparation of 6-propionamido-veratramide.- A dropwise additionof 10.1 grams (0.1 mole) of propionyl chloride Was made to a solution of19.6 grams (0.1 mole) of o-amino-veratramide in 50 ml. of pyridine. Thesolution was held at a temperature below 10 C. during the addition.Precipitation was initiated about 5 minutes after the completion of theaddition and the resultant mixture was permitted to attain roomtemperature. The mixture was combined with 400 ml. of Water, withconstant stirring, and the crystalline product was removed byfiltration. The filter cake was washed with water and then dried overphosphorus pentoxide. This procedure afforded 21.6 grams of6-propionamido-veratramide which was separated as a white amorphoussolid. The melting point of this solid was 196l97 C. and it representeda yield of 13 86.5 percent. Recrystallization of a 2.5 gram portion ofthe white solid from 60 ml. of methanol yielded 2.3 grams of whitecrystals which were used as the analytical sample. The recrystallizedsample had a melting point of 196- 197 C., and was found to behomogeneous by thin layer chromatography.

Analysis.-Calcd for C H N O (percent): C, 57.13; H, 6.39; N, 11.11.Found (percent): C, 57.09; H. 6.27; N, 11.04.

Part D: Preparation of 2ethyl-6,7-dimethoxy-4(3H)- quinazolinone.-Amixture containing 17.1 grams (0.068 mole) of6-propionamido-veratramide, 4.45 grams (0.079 mole) of potassiumhydroxide and 100 ml. of absolute ethanol was stirred and refluxed undera nitrogen atmosphere for 90 minutes. The resultant clear yellowsolution was evaporated to remove the bulk of the ethanol and theresidue was added to 500 ml. of water and acidified with glacial aceticacid to pH of 6. The mixture was filtered and the filter cake was washedwith ethanol and water. The solid was dried over phosphorus pentoxideand 16.0 grams of product were obtained as a white, microcrystallinesolid. The white solid, which represented a yield of 100 percent, had amelting point of 252-253 C. and was homogeneous by thin layerchromatography.

Part B: Preparation of 2-ethyl-4-ch1oro-6,7-dimethoxyquinazoline.Amixture of 16.0 gram (0.068 mole) of2-ethyl-6,7-dimethoxy-4-(3H-quinazolinone in 160 ml. of phosphorusoxychloride was stirred with reflux for 3.5 hours. The resultingsolution, which was formed after 2.5 hours of stirring at reflux, wasconcentrated to an oily residue which was dissolved in 500 ml. ofmethylene chloride. This solution was added to 500 ml. of concentratedammonium hydroxide solution with constant stirring. The methylenechloride layer was drawn off and the resultant aqueous phase wasextracted with two 200 ml. portions of methylene chloride. The combinedorganic phases were washed with two 200 ml. portions of water and driedover sodium sulfate. Evaporation of the methylene chloride yielded 15.3grams of 2-ethyl-4-chloro-6,7-dimethoxyquinazoline as a homogeneousyellow amorphous solid. The solid evidenced a melting point of 150-154C. and represented a yield of 89 percent. An analytical sample wasobtained by recrystallization from a methylene chloride-hexane mixture.The product, which was separated as small colorless needles, evidenced amelting point of 155-156.5 C. and was homogeneous by thin layerchromatography.

Part F: Preparation of4-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid,isobutyl ester- A mixture of 5.0 grams (0.02 mole) of 2-ethyl-4-chloro-6,7-dimethoxyquinazoline and 7.43 grams (0.04 mole) ofpiperazine-l-carboxylic acid, isobutyl ester was dissolved in 50 ml. ofabsolute ethanol and was stirred at reflux for 1 hour. The resultantclear solution was concentrated to a crystalline residue and mixed with150 m1. of boiling hexane. The resultant mixture was filtered and thefiltrate was concentrated. On cooling, 6.4 grams of 4-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid, isobutyl esterwas deposited as a white microcrystalline solid which evidenced amelting point of 98-101 C. and was homogeneous by thin layerchromatography. This amount represented a yield of 79.5 percent. Ananalytical sample was obtained by a further recrystallization fromhexane to yield a product comprised of white needles which evidenced amelting point of 96-97 C.

Example IL-Preparation of4-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)-piperazine=1-carboxylic acid,isobutyl ester hydrochloride The free base was dissolved in .ethylacetate and anhydrous hydrogen chloride was passed into the solution toyield the hydrochloride as a white solid with a melting point of 218-220C. which temperature was also the decomposition point. The yield in thisprocedure was 96.5 percent.

Example III.-Preparation of 2-ethyl-4-amino-6,7-

dimethoxyquinazoline Parts A, B, C, D and E of Example I were repeatedto yield 5 .0 grams of 2-ethyl-4-chloro-6,7-dimethoxyquinazoline.

A mixture of 5.0 grams (0.02 mole) of 2-ethyl-4-chloro-6,7-dimethoxyquinazoline and 70 ml. of saturated ethanolic ammoniasolution was heated at C. for 18 hours. The reaction mixture was thenfiltered after which the solid material was Washed well with ethanol anddried in air to yield 4.1 grams of a crystalline solid which evidenced amelting point of 248-253 C. The crystalline solid was a mixture of thedesired product and its hydrochloride salt. The solid was slurried inconcentrated ammonium hydroxide, filtered, and recrystallized from 75ml. of ethanol to separate 2.6 grams of a white crystalline solid whichevidenced a melting point of 238-239 C. The white crystalline solid,which represented a yield of 56 percent, was homogeneous by thin layerchromatography.

Analysis.-Calcd for C H N C (percent): C, 61.78; H, 6.48; N, 18.02.Found (percent): C, 61.75; H, 6.58; N, 17.69.

Example IV.-Preparation of 4-amino-2-methyl-6,7- dimethoxyquinazolinehydrochloride A mixture of 5.0 grams (0.0225 mole) of Z-methyl-6,7-dimethoxy-4(3H)-quinazoline (prepared by the method of G. N. Walker,I. Am. Chem. Soc., 77, 6698 (1955)) and 50 ml. of phosphorus oxychloridewas stirred at reflux for 35 minutes. The resultant solution was cooledand filtered and the solid was washed with hexane and dried. Thisprocedure yielded 6.7 grams of crude 4-chloro-2-methyl-'6,7-dimethoxyquinazoline hydrochloride which evidence amelting point of 183-185" C. The crude material was combined with 70 ml.of ethanol which had been saturated with ammonia and the mixture washeated at 140 C. for 1-8 hours. The resultant mixture was chilled andfiltered. The solid was washed with ethanol and yielded 5.3 grams of4-amino-2-methyl-6,7-dimethoxyquinazoline hydrochloride. This materialwas obtained in a yield of 93 percent based on quinazoline and evidenceda melting point of 278-280 C. at which temperature it was found todecompose.

Example V.-Preparation of 4-dimethylamino-6,7-dimethoxyquinazoline PartA: Preparation of 6,7-dimethoxy-4-(3H)-quinazolinone.The procedures ofPart A and Part B of Example I were carried out to prepare6-aminoveratramide.

A mixture of 25.4 grams (0.129 mole) of 6-aminoveratramide and 50 ml. of97 percent formic acid was stirred at reflux for 2 hours to yieldcomplete dissolution of the solid. Upon cooling to room temperature,crystallization occurred. The mixture was diluted with 200 ml. ofethanol and filtered. The filter cake was dried and 21.5 grams of whitesolid was obtained. The white solid, which evidenced a melting point of293-294 C., was homogeneous by thin layer chromatography. The yieldobtained by this procedure was 81 percent. An analytical sample wasobtained by recrystallization from dimethylformamide and white needles,which metled at 296-298 C., were obtained.

Analysis.Calcd for C H N O (percent): C, 58.25; H, 4.89; N, 13.58. Found(percent): C, 58.10; H, 5.01; N, 13.49.

The hydrochloride was prepared by the method of Example II and evidenceda melting point of 260-261 C.

Analysis.-Calcd for C 'H N o HCl (percent): C, 49.49; H, 4.57; N, 11.54;Cl, 14.61. Found (percent): C, 49.68;I-I, 4.76; N, 11.33; Cl, 14.85.

Part B: Preparation of 4-chloro-6,7-dimethoxyquinazo line.A mixture of21.5 grams (0.104 mole) of 6,7-dimethoXy-4(3H)-quinazolinone and 215 ml.of phosphorous oxychloride was stirred at reflux for 4 hours. A completesolution resulted after one hour. The solution was concentrated to anoily residue which was added slowly to 400 ml. of concentrated ammoniumhydroxide solution. The resultant solid was filtered, washed well withwater and dried in air to yield 19.5 grams of solid material whichevidenced a melting point of 181-185 C. Upon recrystallization fromethanol, 14.5 grams of a white crystalline product, which evidenced amelting point of 184 186 C., was produced in a yield of 62.5 percent.

Part C: Preparation of 4-dimethylamino-6,7-dimethoxyquinazoline.Astainless steel pressure bottle was charged with 4.0 grams (0.0179 mole)of 4-chloro-6,7-dimethoxyquinazoline and 90 ml. of a 1:2dimethylamine-ethanol solution. The bottle was heated at 130 C. for 4hours. Upon cooling, 1.7 grams of white crystalline4-dimethylamino-6,7-dimet.hoxyquinazoline was deposited. The product,which manifested a melting point of 157159 C., was obtained in a yieldof 41 percent. The filtrate was evaporated to dryness and the cruderesidue, which totalled 3.3 grams, was eluted from a Florisil columnwith benzene (7X 150 ml. fractions) to separate a further yield of 1.2grams of crystalline material which manifested a melting point of158-160 C. This was identical with the first product crop and both cropsshowed a single spot upon thin layer chromatography. The total yield forthis procedure was 70 percent.

Analysisw-Calcd for C H N O (percent): C, 61.78; H, 6.48; N, 18.02.Found (percent): C, 61.97; H, 6.37; N, 18.05.

Example VI.Preparation of 4-(6,7-dimethoxyquinazolin 4 yl) piperazine lcarboxylic acid, isobutyl ester The procedures of Parts A and B ofExample V were used to prepare 4-chloro-6,7-dimethoxyquinazoline Asolution containing 10.0 grams (0.0446 mole) of 4 chloro 6,7dimethoxyquinazoline and 16.6 grams (0.0892 mole) ofpiperazine-l-carboxylic acid, isobutyl ester dissolved in 100 ml. ofabsolute ethanol was stirred at reflux for 1 hour. Upon cooling theproduct crystallized and the mixture was filtered. The filter cake waswashed with water and dried over phosphorOus pentoxide to yield 15.1grams of white crystalline solid product which was homogeneous by thinlayer chromatography. The product, which evidenced a melting point of151152 C., was obtained in 90.5 percent yield.

AnaIysis.Calcd for C H O N (percent): C, 60.94; H, 7.00; N, 14.96. Found(percent): C, 60.95; H, 6.98; N, 14.74.

Example VII.-Preparation of 4-piperazinyl-6.7-

dimethoxyquinazoline The procedure of Parts A and B of Example V wereused to prepare 4-chloro-6,7-dimethoxyquinazoline.

A solution of 20.5 grams (0.09 mole) of 4-chloro-6,7-dimethoxyquinazoline dissolved in 1 liter of chloroform was added,dropwise, over a 24 hour period, to a stirred, refluxing solution of77.4 grams (0.9 mole) of anhydrous piperazine dissolved in 1 liter ofabsolute ethanol. The resultant solution was evaporated to a crystallineresidue which was dissolved in 600 ml. of water. The aqueous solutionwas extracted with four 200 ml. portions of methylene chloride and thecombined extracts were dried over sodium sulfate. Evaporation of thesolvent afiorded 23.7 grams of a crystalline residue which melted at 143147 C. The residue was recrystallized from 150 ml. of ethyl acetate toseparate 18.2 grams of white rods, with a melting point of 147148 C.,which were homogeneous by thin layer chromatography. Furtherrecrystallization from ethyl acetate provided an analytical sample, aswhite rods, which melted at 150151.5 C. The procedure afforded a yieldof 74 percent.

Analysis.Calcd for C H N O (percent): C, 61.29; H, 6.61; N, 20.43. Found(percent): C, 61.24; H, 6.40; N, 20.26.

16 Example VIII.Preparation of 4-(4-isovaleryl-l-piperazinyl-6,7-dimethoxyquinazoline The procedure of Example VII was used toprepare 4-piperazinyl-6,7-dimethoxyquinazoline.

A solution of 0.635 gram (0.0051 mole) of isovaleryl chloride dissolvedin 5 ml. of methylene chloride was added to a solution of 1.37 grams(0.005 mole) of 4-piperazinyl-6,7-dimethoxyquinazoline and 0.51 gram(0.0051 mole) of triethylamine dissolved in 20 ml. of methylene chlorideover a period of 15 minutes. During the addition the solution was cooledin an ice bath. The mixture was stirred at room temperature for 20minutes and 60 ml. of methylene chloride was added. The solution wasthen extracted with three 60 ml. portions of water. The organic phaseWas dried over sodium sulfate and evaporated to 1.6 grams of gummyresidue. The residue was recrystallized from 1:9 benzenehexane todeposit 1.15 grams of crystalline solid which evidenced a melting pointof -126 C. and which was homogeneous by thin layer chromatography. Theprocedure afforded a yield of 64 percent.

Analysis.-Calcd for C H O N (percent): C, 63.66; H, 7.31; N, 15.63.Found (percent): C, 63.55; H, 7.29; N, 15.43.

Example IX.-Preparation of 4-(2-methyl-6,7-dimethoxyquinazolin 4 yl)piperazine 1 carboxylic acid, isobutyl ester A 5.0 gram sample (0.0225mole) of 2-methyl-6,7-dimethoxy 4 (3H) quinazolinone was chlorinatedwith phosphorous oxychloride according to the procedure given in ExampleIV. The resultant crude solid was heated at C. for 4 hours together with12.6 grams (0.0675 mole) of piperazine-l-carboxylic acid, isobutyl esterand 40 ml. of ethanol. The resultant mixture was cooled and filtered.The filter cake, which had a total weight of 3.0 grams, was dissolved inwater and the solution was made basic with ammonium hydroxide solution.The resultant precipitate was triturated with chloroform after which thechloroform washes were evaporated. The residue, after evaporation, wasrecrystallized from methanol-water. This procedure yielded 1.3 grams ofwhite solid which evidenced a melting point of l31132 C. and washomogeneous by thin layer chromatography.

The filtrate which was obtained from the original reaction mixture wasevaporated to dryness and the resultant gummy residue was treatedaccording to the above procedure. A yield of 1.2 grams of white solid,which evidenced a melting point of 131132 C., was obtained. Thismaterial was identical with the material produced from the filter cake.The total yield of product by this procedure was 29 percent and 2.5grams of product was obtained.

The procedure of Example II was carried out using the free base. Thehydrochloride was obtained as a white solid which evidenced a meltingpoint of 228 C. This temperature was also the decomposition point.

Analysis.Cald for C H N O -HCl- /2H O (percent): C, 54.23; H, 7.05; N,12.65; Cl, 8.00. Found (percent): C, 54.27; H, 7.25; N, 12.58; Cl, 8.02.

Example X.Preparation of 4-amino-6,7-ethylenedioxyquinazoline Theprocedure of Example V was carried out except that4,5-ethylenedioxy-o-aminobenzoic acid amide was used in the proceduredescribed in Part A of Example V. The resultant product, which wasrecrystallized from a mixture of ethanol and ether, evidenced a meltingoint of 234-236 C. The hydrochloride, which was prepared by theprocedure of Example II, evidenced a melting point of 278-281 C.

Example XI.-Preparation of 2-amino-6,7- diisopropoxyquinazoline Theprocedure of Example V was carried out except that the starting materialwas 4,5-di-isopropoxy-o-aminobenzoic acid amide. The resultant material,which was crystallized from benzene, evidenced a melting point of147.5148.5 C. The hydrochloride, which was prepared by the methodoutlined in Example 11, evidenced a melting point of 250-251 C.

Example XII.Preparation of 4-arnino-7- methoxyquinazoline The procedureof Example V was carried out except that 4-methoxy-o-aminobenzoic acidamide was used as a starting material. The resultant product, which wascrystallized from methanol, evidenced a melting point of 270-271 C. andthe corresponding hydrochloride evidenced a melting point of 255-256 C.

Example XIII.Preparation of substituted 6,7- dimethoxyquinazolines Theprocedure described in Example V was followed in preparing the compoundslisted below except that the appropriate amine base was substituted as areagent in place of diethylamine on the same molar basis as before. Thecorresponding hydrochlorides were prepared by the method of Example II.

4-amino-6,7-dimethoxyquinazoline, M.P. 205-207 C.; recrystallized fromwater; 2-amino-6,7dimethoxyquinazoline hydrochloride, M.P. 275 C.

4 methylamino-6,7-dimethoxyquinazoline, MP. 206- 208 C.; recrystallizedfrom ethanol; 4-methylamino-6,7- dimethoxyquinazoline hydrochloride,M.P. 264-265 C.

4-ethylamino-6,7-dimethoxyquinazolinc, M.P. 223-224 C.; recrystallizedfrom methanol; 4-ethlyamino-6,7-dimethoxyquinazoline hydrochloride, M.P.261-262 C.

4 propylamino-6,7-dimethoxyquinazoline, M.P. 207- 208 C.; recrystallizedfrom ethyl acetate; 4-propylamino- 6,7-dimethoxyquinazolinehydrochloride, M.P. 246-248 C.

4-isopropylamino-6,7-dimethoxyquinazoline, M.P. 248- 250 C.;recrystallized from ethanol; 4-isopropylamino- 6,7-dimethoxyquinazolinehydrochloride, M.P. 250 C. (decomposition) 4 cyclopropylamino6,7-dimethoxyquinazoline, M.P. 237-239 C.; recrystallized from ethylacetate; 4-cyclopropylamino 6,7 dimethoxyquinazoline hydrochloride, M.P.2535-254 C. (decomposition).

4 phenylamino-6,7-dimethoxyquinazoline, M.P. 236- 238 C.;4-phenylamino-6,7-dimethoxyquinazoline hydrochloride, M.P. 2S9-260 C.

4 benzylamino-6,7-dimethoxyquinazoline, M.P. 230- 231 C.; recrystallizedfrom ethanol; 4-benzylamino-6,7- dimethoxyquinazoline hydrochloride,-M.P. 250C.

4 (2 phenylethylamino) 6,7-dimethoxyquinazoline, M.P. 190-191 C.;recrystallized from water; 4-(2-phenylethylamino) 6,7dimethoxyquinazoline hydrochloride, 239-241 C.

4-diethylamino-6,7-dimethoxyquinazoline, M.P. 112- 114 C.; 4diethylamine 6,7 dimethoxyquinazoline hydrochloride, M.P. 224 C.

4-dipropylamino-6,7-dimethoxyquinazoline, M.P. 147- 148 C.;recrystallized from methanol-Water; 4-dipropylamino 6,7dimethoxyquinazoline hydrochloride; M.P. 207 C. (decomposition).

4-(4-mo rpholino) -6,7-dimethoxyquinazoline, M.P. 139- 140 C.;recrystallized from chloroform-isopropyl ether; 4(4-morpholino)-6,7-dimethoxyquinazoline hydrochloride, M.P. 225-256 C.

4 (4 [B-hydroxyethyl}l-piperidino)-6,7-dimethoxyquinazoline, M.P.147-150 C.; 4-(4-[B-hydroxyethyl]-1-piperidino)-6,7-dimethoxyquinazoline hydrochloride, M.P. 199-201 C.(decomposition).

4 (4-hydroxypiperidino-1-)6,7dimethoxyquinazoline; recrystallized fromisopropyl alcohol, M.P. 201-201.5 C.; 4 (4 hydroxypiperidino1-)6,7-dimethoxyquinazoline hydrochloride, M.P. 233 C. (decomposition).

4 (4 phenylpiperidino-1-)6,7-dimethoxyquinazoline,

18 M.P. 159-160" C.; recrystallized from methanol; 4-(4-phenylpiperidino-1-)6,7-dimethoxyquinazoline hydrochloride, M.P. 214-215C. (decomposition).

4 (4-carboxypiperidino-1-)6,7-dimethoxyquinazoline, M.P. 254-256 C.

Example XIV.-Preparation of substituted 6,7- dimethoxyquinazolines Thefollowing compounds Were prepared by the procedures given in Example VI,Example VIII, or Example IX. The appropriate ester or chloride was usedin place of the piperazine-l-car'boxylic acid, isobutyl ester or theisovaleryl chloride on the same molar basis as before. The correspondinghydrochloride was produced by the method of Example II.

4-(piperazino-1-)-6,7-dimethoxyquinazoline, M.P. 151.5 C.;recrystallized from ethyl acetate; 4-(piperazino- 1)6,7-dimethoxyquinazoline hydrochloride, M.P. 229- 230 C.(decomposition).

4-(4 methylpiperazino 1-)-6,7-dimethoxyquinazoline, M.P. 159-160 C.;recrystallized from methylene chlorideisopropyl ether;4-(4-methylpiperazino-l-)-6,7-dimethoxyquinazoline hydrochloride, M.P.300-301 C. (decomposition).

4 (4 allyl-piperazino-1-)-6,7-dimethoxyquinazoline, M.P. 128-130 C.;recrystallized from isopropyl ether;4-(4-allyl-piperazino-1-)-6,7-dimethoxyquinazoline hydrochloride, M.P.239-242 C. (decomposition).

4 (4 ,8 hydroxyethylpiperazino-1-)-6,7-dimethoxyquinazoline, M.P. -158C.; recrystallized from ethyl acetate;4-(4-l3-hydroxyethylpiperazino-1-) 6,7-dimethoxyquinazolinehydrochloride, M.P. 230-2325 C. (decomposition).

4 (4-phenylpiperazin0 1-)-6,7-dimethoxyquinazoline, M.P. 152.5-156 C.;recrystallized from methanol-Water; 4(4-phenylpiperazino-1)-6,7-dimethoxyquinazoline hydrochloride, M.P.221-223 C. (decomposition).

4 (4-[6,7 dimethoxy-4-quinazolinyl]-piperazino-l-)-6,7-dimethoxyquinazoline, M.P. 264-265 C.; recrystallized fromchloroform-methanol; 4-(4-[6,7-dimethoxy4-quinazolylJ-piperazino-1-)-6,7-dimethoxyquinazoline hydrochloride, M.P.253-255 C. (decomposition).

4 r (6,7 dimethoxyquinazolin 4-yl)-piperazino-1-carboxylic acid, ethylester, M.P. 145-147 C.; recrystallized from benzene-hexane;4-(6,7-dimethoxyquinazolin-4-yl)- piperazine-l-carboxylic acid, ethylester hydrochloride, M.P. 215-216 C.

4 (6,7 dimethoxyquinazolin 4-yl)-piperazino-1-carboxylic acid, propylester, M.P. 131-133 C.; recrystallized from methanol-water;4-(6.7-dimethoxyquinazolin-4- yl-)-piperazine-1-carboxylic acid, propylester hydrochloride, M.P. 229 C. (decomposition).

4 (6,7 dimethoxyquinazolin 4-yl)-piperazine-1-carboxylic acid, isopropylester.

4 (6,7 dimethoxyquinazolin 4-yl)-piperazine-1-carboxylic acid, butylester, M.P. 129130 C., recrystallized from methanol-water;4-(6,7-dimethoxyquinazolin-4-yl)- piperazine-l-carboxylic acid, butylester hydrochloride, M.P. 199-200 C.

4-(6,7 dimethoxyquinazolin 4 yl)-piperazine-1- carboxylic acid, isobutylester, M.P. 151152 C.; recrystallized from methanol;4-(6,7-dimethoxyquinazolin- 4-yl)-piperazine-1-car-boxylic acid,isobutyl ester hydrochloride, M.P. 217 C. (decomposition).

4-(6,7 dimethoxyquinazolin 4 yl)-piperazine-lcarboxylic acid, pentylester, M.P. 153-154 C.; recrystallized from methanol;4-6,7-dimethoxyquinazolin-4-yl)- piperazine-l-carboxylic acid, pentylester hydrochloride, M.P. 212-212.5 C. (decomposition).

4-(6,7 dimethoxyquinazolin 4 yl)-piperazine-1- carboxylic acid, hexylester, M.P. 143.5145 C.; recrystallized from methanol-water;4-(6,7-dimethoxyquinazolin- 4-yl)-piperazine-1-carboxylic acid, hexylester hydrochloride, M.P. 187-187.5 C. (decomposition).

4-(6,7 dimethoxyquinazolin 4 yl)-piperazine-1- carboxylic acid,tetrahydrofurfuryl ester, M.P. 139140 C.; recrystallized frombenzene-hexane.

4-(6,7 diniethoxyquinazolin 4 yl)-piperazine-1- earboxylic acid, phenylester, M.P. 154-155 C.; recrystallized from acetone-water;4-(6,7-dimethoxyquinazolin-4- yl)-piperazine-1-carboxylic acid, phenylester hydrochloride, M.P. 231 C.

4-(6,7 dimethoxyquinazolin 4 yl)-piperazine-1- carboxylic acid, benzylester, M.P. 132-133.5 C.; recrystallized from methanol-water;4-(6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid, benzylester hydrochloride, M.P. 198-199" C.

4-(4 acetylpiperazino 1)-6,7-dimethoxyquinazoline, M.P. 186 C.;recrystallized from isopropanol-isopropyl ether;4-(4-acetylpiperazino-1)-6,7-dimethoxyquinazoline, hydrochloride M.P.224-225 C. (decomposition).

4-(4-propionylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 150-151C.;recrystallized from benzanehexane; 4-(4-propionylpiperazino-1)6,7-dimethoxyquinazoline hydrochloride, M.P. 216-217 C.

4-(4-propionylpiperazino-l) 6,7 dimethoxyquinazoline, M.P. 134135 C.;recrystallized from benzene-hexane;4-(4-butyrylpiperazino-1)-6,7-dimethoxyquinazoline hydrochloride, M.P.179181 C. (decomposition).

4-(4 isobutyrylpiperazino-l) 6,7 dimethoxyquinazo line, M.P. 172-173 C.;recrystallized from benzenehexane; 4-(4 isobutyrylpiperazino-l)6,7-dimethoxyquinazoline hydrochloride, M.P. 210-211 C.

4-(4-valerylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. l30.5-l32 C.;recrystallized from ethyl acetatehexane; 4-(4valerylpiperazino-l)-6,7-dimethxyquinazoline hydrochloride, M.P.209-210" C.

4-(4-heptanoylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 136-138 C.;recrystallized from methanolwater; 4-(4heptanoylpiperazino-l)-6,7-dimethoxyquinazoline hydrochloride, M.P.157-158 C. (decomposition).

4-(4 benzoyl 1 piperazinyl)-6,7-dimethoxyquinazoline, M.P. 221-223 C.;recrystallized from methanol; 4-(4 benzoyl 1piperazinyl)-6,7-dimethoxyquinazoline hydrochloride, M.P. 183-185 C.

4-(4 acrylylpiperazino-l) 6,7 dimethoxyquinazoline, M.P. 127-129 C.;recrystallized from benzene-hexane; 4-(4 acrylylpiperazino-l) 6,7dimethoxyquinazoline hydrochloride, M.P. 102-l04 C.

4-(4-(2-fur0y1) piperazino-l) 6,7-dimethoxyquinazoline, M.P. 159-161 C.;recrystallized from benzene-hexane; 4-(4 (2turoyl)-piperazino-1)-6,7-dimethoxy-quinazoline hydrochloride, M.P.222223 C.

4-(4 dimethylformamidopiperazino-1)-6,7-dirnethoxyquinazoline, M.P.147-148.5 C.; recrystallized from benzene-isopropyl ether;4-(4-dimethylformamidopiperazino- 1)-6,7-dimethoxyquinazolinehydrochloride; M.P. 167- 168 C.

4-(trifiuoroacetylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 19l-192C.; recrystallized from methylene chloride-isopropyl ether; 4-(4-trifluoro acetylpiperazino- 1 6,7-dimethoxyquinazoline hydrochloride,M.P. 225-226 C.

4-(4 trichloroaeetylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 84-88"C.; recrystallized from dimethylformamide-water; 4(4-trichloroacetylpiperazino-1)-6,7- dimethoxyquinazoline hydrochloride,M.P. 243-244 C.

4-(4 methylsulfonylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 239-240C.; recrystallized from chloroform-methanol;4-(4-methylsulfonylpiperazino-1) 6,7- dimethoxyquinazolinehydrochloride, M.P. 246 C. (decomposition).

4-(4 phenylsulfonylpiperazino-1) 6,7 dimethoxyquinazoline, M.P. 186-187"C.; recrystallized from benzene; 4-(4phenylsulfonylpiperazino-l)-6,7-dimethoxyquinazoline hydrochloride; M.P.236237 C. (decom position).

4-(homopiperazino-1) 6,7 dimethoxyquinazoline, M.P. 146.5-148 C.;recrystallized from ethyl acetate.

4- 6,7 dimethoxyquinazolin-4-yl)-homopiperazino-1- carboxylic acid,isobutyl ester, M.P. lO9-112 C.; recrystallized from isopropylether-hexane; 4-(6,7-dirnethoxyquinazoline-4-yl)-hornopiperazino 1carboxylic acid, isobutyl ester hydrochloride, M.P. 214-215 C.(decomposition).

Example XV.Preparation of substituted 4-(6,7-dimethoxyquinazolin-4-yl-piperazinel-carboxylic acid,

isobutyl esters The procedure described in Example I was followed inpreparing the compounds listed below except that the appropriate acidchloride was substituted as a reagent in place of the propionyl chlorideon the same molar basis as before.

The corresponding hydrochlorides were prepared by the method of ExampleII.

4-(2 trifiuormethyl 6,7 dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid, isobutyl ester, M.P. 132- 133 C.;recrystallized from ethanol;4-(2-trifiuoromethyl-6,7-dimethoxyquinazolin 4yl)-piperazine-1-carboxylic acid, isobutyl ester hydrochloride, M.P.169-171 C.

4-(2 propyl 6,7 dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,isobutyl ester, M.P. -102" C.; recrystallized from hexane:4-(2-propyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,isobutyl ester hydrochloride, M.P. 202-204 C.

4-(2 isopropyl 6,7 dimethoxyquinazoline-4-yl)- piperazine-l-carboxylicacid, isobutyl ester, M.P. 102- 104 C.; recrystallized from hexane;4-(2-isopropyl-6,7- dimethoxyquinazolin-4-yl) piperazine-l-carboxylicacid, isobutyl ester hydrochloride, M.P. 198-199.5 C. (decomposition).

4-(2 t butyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,isobutyl ester, M.P. 899l C.; recrystallized from hexane;4-(2-t-butyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid,isobutyl ester hydrochloride, M.P. 180-181.5 C.

4-(2 phenyl 6,7 dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,isobutyl ester, M.P. 164-166 C.; recrystallized from methanol;4-(2-phenyl-6,7-dimethoxyquinazolin-4-yl) piperazine-l-carboxylic acid,isobutyl ester hydrochloride, M.P. 227-228 C. (decomposition).

4-(2-benzyl-6,7-dimethoxyquinazolinl-yl)-piperazine-lcarboxylic acid,isobutyl ester, M.P. 62-64 C.; recrystallized from dichloromethanehexane; 4-(2-benzyl-6,7- dimethoxyquinazolin-4-yl)piperazine-l-carboxylic acid, isobutyl ester hydrochloric, M.P. 198-199C.

4-(2-phenylethyl-6,7-dimethoxyquinazolin-4-yl)-piperazine-l-earboxylicacid, isobutyl ester, M.P. 100-101 C.; recrystallized frombenzene-hexane; 4-(2-phenylethyl-6,7- dimethoxyquinazolin-4-yl)piperazine-l-carboxylic acid, isobutyl ester hydrochloride, M.P. 191 C.

4 (6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid, isobutylester hydrochloride, M.P. 217 C. (decomposition).

Example XVI.Preparation of 4-aminov 6,7-dimethoxyquinazoline Theprocedures of Example V were used to prepare 4-amino-6,7-dimethoxyquinazoline except that ammonia was used as a reagentin place of the dimethylarnine, on the same molar basis. The resultantcompound, which was recrystallized from water, evidenced a melting pointof 205-207 C. The corresponding hydrochloride, which was prepared by themethod of Example II, evidenced a melting point of 275 C.

Example XVIL-Preparation of 2-substituted-4-amino-6,7-dimethoxyquinazolines The following compounds were preparedby the methods of Example III except that appropriate acid chlorideswere used as reagents in place of the propionyl chloride which was usedin the procedures of Example III.

The corresponding hydrochlorides were prepared by the method of ExampleII.

2-trifiuormethyl-4-amino 6,7 dimethoxyquinazoline, M.P. 284-286 C.;recrystallized from methanol;2-trifiuormethyl-4-amino-6,7-dimethoxyquinazoline hydrochloride, M.P.258-259 C. (decomposition).

2 ethyl4-amino-6,7-dimethoxyquinazoline hydrochloride, M.P. 262-263? C.(decomposition).

2-propyl-4-amino-6,7-dimethoxyquinazoline, M.P. 224- 226 C.;recrystallized from methanol; 2-propyl-4-amino- 6,7-dimethoxyquinazolinehydrochloride, M.P. 258-260 C. (decomposition).

2-isopropyl 4 amino-6,7-dimethoxyquinazoline, M.P. 217-218 C.;2-isopropyl-4-amino-6,7-dimethoxyquinazoline hydrochloride, M.P. 255-257C.

Z-t-butyl-4-amino-6,7-dimethoxyquinazoline hydrochloride, M.P. 272-273C. (decomposition).

2-phenyl-4-amino-6-,7-dimethoxyquinazoline, M.P. 203- 204 C.;recrystallized from methanol; 2-phenyl-4-amino- 6,7-dimethoxyquinazolinehydrochloride, M.P. 258-260 C. (decomposition).

2-benzyl-4-amino-6,7-dimethoxyquinazoline.

2-phenylethyl-4-amino-6,7-dimethoxyquinazoline hydrochloride, M.P.270-271" C. (decomposition).

Example XVIII.Preparation of -2-diethylamino-4-methyl-6,7-dimethoxyquinazoline Part A: Preparation of diethyl4-(2-chloro-6,7-dimethoxyquinazoline)-malonate.A solution of diethylsodiomalonate in dimethylformamide was prepared from 11.5 grams (0.24mole) of a 50% sodium hydride-mineral oil dispersion from which themineral oil had been removed by washing with hexane, 32.0 grams (0.2mole) of diethylmalonate and 100 ml. of dimethylformamide. To thissolution, 51.8 grams (0.2 mole) of 2,4-dichloro-6,7-dimethoxyquinazoline was added. The 2,4-dichloro-6,7-dimethoxyquinazolinewas prepared according to the procedure of F. H. S. Curd et al., J.Chem. Soc. (London), 1759 (1948). The resultant solution was heated at60 C. for 40 hours and was poured into 4 liters of ice water, aftercooling. The resultant mixture was filtered and Washed well with waterin order to separate 61.0 grams of diethyl 4-(2-chloro 6,7dimethoxyquinazolyl)-malonate. This compound evidenced a melting pointof 137- 142 C. and was produced at a 80 percent yield. Recrystallizationof 1.0 gram from 50 ml. of ethanol yielded 600 mg. (60 percent recovery)of material which evidenced a melting point of 160.5162.5 C. Thecompound was shown to be homogeneous by thin layer chromatography usingbenzene-ethyl acetate-5% diethylamine as a solvent system.

Part B: Preparation of 2-chloro-4-methyl-6,7-dimethoxyquinazoline.Asuspension of 30.0 grams (0.0785 mole) of diethyl-4-(2chloro-6-,7-dimethoxyquinazolyl)- malonate in 300 ml. of 1.0 N sodiumhydroxide solution was prepared and was refluxed with vigorous stirringfor one hour. A complete solution occurred after 25 minutes and aprecipitate was formed after 40 minutes of refluxing and stirring. Thecooled reaction mixture was filtered in order to separate 8.7 grams of2-chloro-4-methyl-6,7- dimethoxyquinazoline. The product, which wasproduced at a yield of 46.5 percent, evidenced a melting point of 179181C. Recrystallization of a portion of the product from methanol providedan analytical sample which melted at 183185 C. and which was homogeneousby thin layer chromatography.

Analysis.-Calcd. for C H N O Cl (percent): C, 55.35; H, 4.64; N, 11.74;Cl, 14.85. Found (percent): C, 55.59; H, 4.67; N, 11.69; Cl, 14.80.

Part C: Preparation of2-diethylamino-4-methyl-6,7-dimethoxyquinazoline.-A stainless steelpressure vessel was charged with 4.0 grams (0.0168 mole) of 2-chloro-4-methyl-6,7-dimethoxyquinazoline, 40 ml. of diethylamine and 40 ml. ofethanol. The pressure vessel was immersed in a heating bath which wasmaintained at 130 C. for 3 hours. The resultant solution was filtered inorder to remove 800 milligrams of unidentified solid material and thefiltrate was evaporated to dryness. The resultant solid was dissolved in100 ml. of boiling hexane and 1.2 grams of insoluble material wasremoved by filtration. The insoluble material evidenced a melting pointof 81-106 C. The filtrate was concentrated to 25 ml. and chilled andfiltered to separate 2.35 grams of pale yellow crystalline solidproduct. The product, which melted at 97 C., was obtained in a yield of51 percent and was homogeneous by thin layer chromatography.

Analysis.-Calcd. for C H N O (percent): C, 65.43; H, 7.69; N, 15.26.Found (percent): C, 65.69; H, 7.83; N, 15.05.

Part D: Preparation of the hydrochloride salt of2-diethylamino-4-methyl-6,7-dimethoxyquinazoline.-The hydrochloride saltwas prepared by dissolving 2.35 grams of the free base in 30 ml. ofethanol and passing hydrogen chloride gas through the solution for 10minutes. After filtration the resultant solid was washed with ether anddried. A pale yellow solid which consisted of 2.15 grams of2-diethylamino-4-methyl-6,7-dimethoxyquinazoline hydrochloride wasobtained. The melting point of the solid, which was obtained at theyield of 82.5 percent, was 220'- 221 C.

Analysis.--Calcd. for C H N 0 -HCl (percent); C, 57.78; H, 7.11; N,13.47; Cl, 11.37. Found (percent): C, 57.79; H, 7.12; N, 13.19; Cl,11.26.

Example XIX.Preparation of 2-amino-4-methyl- 6,7-dimethoxyquinazoline Amixture of 19.0 grams (0.0821 mole) of 2-amino- 4,5dimethoxyacetophenone hydrochloride and 19.0 grams (0.45 mole) ofcyanamide was heated to 50 C. for 45 minutes. The dimethoxyacetophenonewas btained by the method of D. Bar and Erb-Debryne, Ann. Pharm.,France, 16, 235 (1958). A complete solution resulted after 20 minutesand the reaction mixture solidified after 30 minutes. The solid materialwas dissolved in 600 ml. of water and the solution was made basic usingconcentrated ammoniu mhydroxide solution. The basic mixture was chilledto 0 C. Upon cooling, the resultant solid material was collected byfiltration, washed with water and dried to produce 19.2 grams of crudematerial with a melting point of 2l22l6 C. Recrystallization from 700ml. of hot water produced 15.0 grams of beige amorphous solid,2-amino-4-methyl-6,7- dimethoxyquinazoline. The material, which wasproduced in 83.5 percent yield, evidenced a melting point of 218- 220 C.and presented a single Spot by thin layer chromatography.

Analysis.Calcd. for C H N O (percent) C, 60.26; H, 5.98; N, 19.15. Found(percent): C, 59.66; H, 5.72; N, 18.84.

Example XX.Preparation of 2-amino-4-methyl6,7-

dimethoxyquinazoline hydrochloride The hydrochloride Salt was preparedby dissolving 3.0 grams (0.0137 mole) of 2-amino 4methyl-6,7-dimethoxyquinazoline in 230 ml. of hot ethanol and passinghydrogen chloride gas through the olution for 10 minutes. Upon coolingand filtration, 3.1 grams of amorphous 2-amino 4 methyl 6,7dimethoxyquinazoline hydrochloride was obtained. The product, whichmelted at 282283 C. (decomposition), was obtained in 89.4 percent yield.A single spot, identical with the spot obtained with the free base, wasobtained by thin layer chromatography.

Analysis.Calcd. for C H N O -HCl (percent): C, 51.67; H, 5.52; N, 16.43;Cl, 13.86. Found (percent): C, 51.44; H, 5.47; N, 16.39; Cl, 13.60.

23 Example XXI.-Preparation of 2-alkylamino-4-alkyl-6,7-dialkoxyquinazolines 24 of Example II, III, IV and V. Thesecompounds are listed in Table II and Table III.

The following compounds were prepared by the TABLE II methods of ExampleXVIII except that appropriate A /N\\ IR amines were used as reagents inplace of the diethyl- I 1 amine used in the procedures of Example XVIII.Sub- N stantially identical molar ratios were employed.

Z-dimethylamino 4 methyl 6,7 dimethoxyquinl azoline, M.P. l3l-l33 C.;Z-dimethylamino 4 methyl- 6,7-dimethoxyquiuazoline hydrochloride, M.P.258 C. It) R1 B3 2 methyl 4(4allyl-piperazino-l-)-6,7-dimethoxyquinazoline, M.P. 138l40 C.; 2methyl 4 (4-allyl- TABLE III piperazino-l-) 6,7 dimethoxyquinazolinehydrochlo- A R ride, M.P. 238240 C. 1

4 (4 methyl 6,7 dimethoxyquinazolin 2 yl)- B N piperazine l carboxylicacid, ethyl ester, M.P. 153- 155 C.; 4 (4 methyl 6,7 dimethoxyquinazoli-2- i yl)-piperazine l carboxylic acid, ethyl ester hydrochloride, M.P.247 0.

4 (4 methyl 6,7 dimethoxyquinazolin 2 yl)- piperazine 1 carboxylic acid,phenyl ester, M.P. 201- 203 C.; 4 (4 methyl 6,7 dimethoxyquinazolin-2-R4 yl)-piperazine 1 carboxylic acid, phenyl ester hydror chloride, M.P.237.5240 C. (decomposition).

4-diethylamino 6,7 dlpentoxyqumazohne 1s prepared CH O H C a by themethods of Example V except that 4,5 dipentoxy- 1 T C CHPCILPUJHQFo-aminobenzoic acid amide is used as the initial reagent. a

Example XXIII.2-hexyl-4-amino-6,7- 8E8: 5 53,: EEPCHHCHTdimethoxyquinazoline r 1 rgo; int g-i-bultyllpllmnyl 2' 2 -nap1t 1y 2hexyl 4 ammo 6,7 dimethoxyqumazolme 1s C a a a 3, y p y prepared by themethods of Example III except that the CH3O CEHF CH2:C OH2 appropriateacid chloride 1s used 1nstead of the propionyl chloride which was usedin Example III.

4 diethylamino 6 propoxyquinazoline is prepared cmo- C2H5O CH=C CHZO OOby the methods of Example V except that 5-pr0p0xy-O- CH3 ammobenzorcacid amide 15 used as the m1t1al reagent. CH3O CH? CH3 CH:CH CH2 O COExample ql jg fy y o2n o omoo;n CH CH-CO la '0 qumazo mes C2115 The 2alkyl 4 alkylammo 6,7 dlalkoxyquinazowho can? Cm? lines, relatedcompounds and their pharmaceutically ac- (in o- Cl'l 0- Cll a-napllthylceptable acid addition salts are prepared by the methods 27 ExampleXXlX.-Bronchodilator activity Conscious female guinea pigs, which hadbeen fasted for 12 hours, received oral or parenteral dosages of thecompound which was to be tested for effectiveness. Control animalsreceived doses of saline solution which did not contain the compoundwhich was under test. Subsequent to this administration, each animal waschallenged with histamine aerosol.

The challenge procedure consisted of spraying a 0.4 percent aqueoussolution of histamine, at a pressure of lb./in. into an 8 x 8 x 12 inchplastic container for one minute. Immediately after the container wassubjected to the histamine spray the animal was placed within it. At theend of one minute of exposure, the respiratory status, which is areflection of bronchoconstriction, was evaluated. Evaluation levels weredesignated and scored as normal breathing (0), slightly deepenedbreathing (1), labored breathing (2), severely labored breathing andataxia (3) and unconsciousness (4). Each group of animals contained 8 to10 individuals and a control group containing the same approximatenumber was used. The scores for the control group and the group whichhad been treated with the compound under test were compared and thedifference was expressed as percent protection.

Thes doses, which were given orally, were 60 rug/kg. and the animalswere challenged with histamine 60 minutes later. The standard compoundused was theophylline which gave percent protection afte ra dose of 60mg./ kg. was administered orally and the animal was challenged one hourlater. When the compounds listed in Table VI below were administeredaccording to this procedure and the animals were challenged accordingly,the following percent protection was observed.

TABLE VI R1 Percent protection C Hr- C HQC H2- 56. C H C H20 Hr- 53. (CH3) 20 H 23. (0 H3) 30- 19.

50. (after 15 minutes).

Percent R4 protection Percent R R1 R protection CH3 I-I- II- 41 CH3CH3CH2- CH3CH2 53 C H; 0 H C H3 27 Percent protection Percent R4protection 0 CsHs- 22 CHaCH2OOC 41 CH2=CHCH2 16 ExampleXXX.Anti-hypertensive activity 29 and by Grimson, K. 8., Proc. Soc. Exp.Biol, 44, 291, (1940) Dogs with spontaneous hypertension were also used.

Blood pressure was measured in the morning prior to drug administrationand, subsequently, at 2, 4, and 24 hours after treatment with thecompound under test. The compounds were administered orally in the formof capsules over a period of 1 to 3 days. The usual dosage was 2.5mgJkg. on the first day and 10, 20 or 40 mg./ kg. on subsequent days.Electrocardiograms were recorded simultaneously with the blood pressure.The response of the hyptertensive dogs to the compounds which wereadministered are shown in Table VII below.

Example XXXI.-Tablets A tablet base is prepared by blending thefollowing ingredients in the proportion by weight indicated:

Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Into this tablet base there is blended suficient4-(6,7-dimethoxyquinazolin-4-yl) piperazine-l-carboxylic acid, isobutylester hydrochloride to provide tablets containing 20, 100 and 250 mg. ofactive ingredient per tablet.

Example XXXII.Capsules A blend is prepared containing the followingingredients:

Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesiumtrisilicate, U.S. P. 5.2 Lactose, U.S.P. 5.2 Potato starch 5 .2.Magnesium stearate A 0.8

Magnesium stearate B 0.35

To this blend is added suflicient4-(6,7-dimethoxyquinazolin-4-yl)-piperazine 1 carboxylic acid, isobutylester hydrochloride to provide capsules containing 20, 100 and 250 mg.of active ingredient per capsule.

Example XXXIII.-Injectable preparation One thousand grams of4-(6,7-dimethoxyquinazolin-4- yl)-piperazine-1-carboxylic acid, isobutylester hydrochloride are intimately mixed and ground with 2500 grams ofsodium ascorbate. The ground dry mixture is placed in vials andsterilized with ethylene oxide after which the vials are sterilelystoppered. For intravenous administration, suificient water is added tothe materials in the vials to form a solution containing 10 mg. ofactive ingredient per milliliter of injectable solution.

Example )O(XIV.Suspension A suspension of2-ethyl-4-amino-6,7-dimethoxyquinazoline is prepared with the followingcomposition:

Eflfective ingredient31.42 g.

70% aqueous sorbitol741.29 g. Glycerine, U.S.P.185.35 g.

Gum acacia (10% solution)-100.0 ml. Polyvinylpyrrolidone-0.5 g.

Distilled water-Sufficient to make 1 liter.

To this suspension, various sweeteners and flavorants may be added toimprove the palatability of the suspension. The suspension containsapproximately 25 mg. of effective agent per milliliter.

Example XXXV.Solution A solution ofZ-ethyl-4-amino-6,7-dimethoxyquinazoline is prepared with the followingcomposition:

Etfective ingredient-30.22 grams Magnesium chloride hexahydrate12.36grams Monoethanolamine-8.85 ml.

Propylene glycol376.0 grams Water, distilled94.0 ml.

The resultant solution has a concentration of effective ingredient of 50mg./ml. and is suitable for parenteral and especially for intramuscularadministration.

Example XXXV-I.Preparation of 4 (6,7dimethoxyquinazolin-4-yl)-piperazine 1 carboxylic acid, Zmethyl-2-chloropropyl ester To a cold (0 C.) solution of 2.74 g. (0.010mole) of 4-piperazinyl-6,7-dimethoxyquinazoline, prepared by the methodof Example VII, and 1.10 g. (0.010 mole) of triethlylamine in 40 ml. ofmethylene chloride was added a solution of 1.7 g. (0.010 mole), of2-methyl-2-chloropropyl chloroformate in 20 ml. of methylene chloride,dropwise, over 10 minutes. After warming to room temperature, the cloudymixture was diluted with 50 ml. of methylene chloride, Washed with 50ml. of water and dried over sodium sulfate. Evaporation of the solventleft 4.3 g. of white crystalline solid, M.P. 140146 C. Recrystallizationfrom acetone-water mixture produced 2.6 g. (63.5%) of the analyticalsample as a white crystalline solid, M.P. 158-159" C.

Analysis.-Calcd. for C H O N Cl (percent): C, 55.80; H, 6.19; N, 13.70;Cl, 8.67. Found (percent): C, 55.50; H, 6.15; N, 13.77; Cl, 8.59.

Example XXXVIL-Preparation of 4 6,7 dimethoxyquinazolin-4-yl)-piperazine1 carboxylic acid, 2-methyl-2-hydroxypropyl ester A solution of 6.0 g.(0.0147 mole) of crude 4-(6,7-dimethoxyquinaZolin-4-yl) piperazine 1carboxylic acid, 2-methyl-2-chloropropyl ester in 225 ml. of 0.1 Nhydrochloric acid was allowed to reflux for 1 hour. The cooled solutionwas extracted with three ml. portions of methylene chloride, and theaqueous phase subsequently made basic with dilute sodium hydroxidesolution and extracted with three 100 ml. portions of methylenechloride. These latter organic extracts were combined, dried over sodiumsulfate and evaporated and the resulting residue recrystallized from achloroform-ethyl acetate mixture to separate 2.1 g. (37%) of whiteprisms M.P. 199-200 C.

Analysis.Calcd. for C H O N (percent): C, 58.45; H, 6.71; N, 14.35.Found (percent): C, 58.36; H, 6.63; N, 14.62.

31 Example XXXVIII.-Preparation of 4-(6,7dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,2-methyl-2-propenyl ester, hydrochloride A mixture of 40.4 g. (0.18mole) of 4-chloro-6,7-dimethoxyquinazoline, prepared by the method ofPart B of Example V, and 33.0 g. (0.18 mole) of piperazine-l-carboxylicacid, 2-methyl-2-propenyl ester in 400 ml. of ethanol was refluxed for 4hours and then evaporated to dryness to leave 73 g. (100%) ofcrystalline solid. This was dissolved in 600 ml. of water and extractedwith four 500 ml. portions of methylene chloride. The combined extractswere evaporated to a volume of 500 ml. and ethyl acetate added untilcrystallization began. Filtration separated 48.0 g. (65%) of thehydrochloride salt of the product as a pale yellow microcrystallinesolid M.P. 2l22l3 C.

(dec.).

A second crop (6.2 g., 8.4%) of product as a yellow microcrystallinesolid, M.P. 2l0-213 C. (dec.) was obtained by concentration of thefiltrate. This material was homogenous by thin layer chromatography.

Example XXXIX.-Preparation of 4 (6,7dimethoxyquinazolin-4-yl)-piperazine-l-carboxylic acid,Z-methyl-2-hydroxypropyl ester To 200 ml. of 50% sulfuric acid-watermixture was added 25 g. (0.0615 mole) of 4-(6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid, 2 methyl-Z-propenyl ester,hydrochloride. The resulting yellow solution was stirred at roomtemperature for 1 hour, poured into 200 g. of ice and made basic with40% sodium hydroxide solution, keeping the temperature below 40 C. Theresulting solution was extracted with four 200 ml. portions of methylenechloride, and the combined organic extracts were extracted with 0.5 Nhydrochloric acid and finally with three 100 ml. portions of water. Thecombined aqueous extracts were made basic with 40% sodium hydroxidesolution and extracted with three 200 ml. portions of methylenechloride. The latter methylene chloride extracts were combined, driedover sodium sulfate and evaporated to leave 18.0 g. (75%) of crystallinesolid M.P. 192-195 C. This was recrystallized from chloroform-ethylacetate mixture to separate 14.5 g. (80%) of analytically pure productM.P. 198-1995 C.

Example XL Five parts, by weight, of the4-(6,7-dimethoxyquinazolin-4-yl)-piperazine-1-carboxylic acid,2-methyl-2-hydroxypropyl ester is dissolved in pyridine at C. and anexcess of propionyl chloride is added, dropwise. At the completion ofthe addition, the resulting mixture is refluxed for 1 hour, cooled,diluted with water and extracted three times with methylene chloride.After washing, the combined methylene chloride layers with dilute acid,they are dried and evaporated to dryness to give4-(6,7-dimethoxyquinazolin-4-yl)-piperazine 1 carboxylic acid, 2-methv1-2-propionoxypropyl ester which is purified by recrystallization ifnecessary.

In a similar manner, the 2-methyl-2-butyryloxypropyl ester, the2-methyl-2-napthoyloxypropyl ester, the 2-methyl-2-benzoxypropyl esterand the Z-methyl-Z-acetoxypropyl ester are prepared.

Example XLI.-Preparation of 4 (6,7 dimethoxyquinazolin-4-yl)-piperazine1 carboxylic acid, 2-dimethylaminoethyl ester Part A: Preparation of4-(6,7-dimethoxyquinazolin-4- yl)-piperazine-1-thiol carboxylic acid,phenyl ester.To a cold (0) solution of 20.0 g. (0.073 mole) of4-piperazinyl-6,7-dimethoxyquinazoline, prepared by the methods ofExample VII and 8.05 g. (0.084 mole) of triethylamine in 150 ml. ofmethylene chloride was added, dropwise, 12.9 g. (0.075 mole) of phenylchlorothiolformate. The resulting mixture was allowed to stir at roomtemperature for minutes and 100 ml. of methylene chloride was added.This solution was washed with two 50 ml. portions of water, dried oversodium sulfate and evaporated to separate 27.46 g. of crude product,M.P. l46151 C. Recrystallization from 500 ml. of methanol separated15.84 g. (53%) of product as a pale yellow microcrystalline solid, M.P.l70-173 C. An additional 5.59 g. (19%), M.P. l66170 C., of product wasobtained from further concentration of the mother liquor.

Part B: Preparation of 4-(6,7-dimethoxyquinazolin-4-yl-6,7dimethovyquinazoline, prepared by the methods of ester.To asuspension of 1.60 g. (0.044 mole) of sodium hydride (60% mineral oildispersion) in 50 ml. of tetrahydrofuran was added 3.92 g. (0.044 mole)of Z-dimethylaminoethanol and the solution refluxed until gas evolutionceased minutes). The resulting solution was cooled to room temperatureand a solution of 4.1 g. (0.01 mole) of 4-(6,7dimethoxyquinazolin-4-yl)-piperazine-l-thiol carboxylic acid, phenylester in 15 ml. of tetrahydrofuran was added at once and the solutionstirred at room temperature for 45 minutes. After dilution with ml. ofwater, the solution was concentrated to remove the tetrahydrofuran, andextracted with four 50 ml. portions of methylene chloride. The combinedextracts were dried over sodium sulfate and evaporated to separate 4.39g. of crude product, M.P. 1l01l4 C. Recrystallization fromethylacetate-hexane mixture gave 2.52 g. of product as an off-whitemicrocrystalline solid M.P. 100-104 C.

The corresponding hydrochloride evidenced a melting point of 230-232 C.

In a similar manner, the compound4-(6,7-dimethoxyquinazolin-4-yl)-piperazine 1 carboxylic acid,Z-diethylaminoethyl ester was prepared, M.P. 93 C.; recrystallized fromisopropyl ether; M.P. of hydrochloride 151 C.

Example XLII When the procedures of Example XLI are employed, using theappropriate aminoalkanol or aminocarbinol in the procedure of Part B ofExample XL-I and the product of Part A of Example XLI, the4-(6,7-dimethoxyquinazolin-4-yl) 1 carboxylic acid,2-methyl-2-ethylmethylaminopropyl ester, the 2-methyl-2-aminopropylester, the 2-methyl-2-anilinopropyl ester, the2-methyl-2-butylaminopropyl ester, the '2-methyl-2-m-tolylaminopropylester, the 2-methyl-2-naphthylaminopropyl ester, the 2-methyl-2-pyrrolidinylpropyl ester, the 2-methyl-2-piperidinylpropyl ester andthe 2-methyl-2-homopiperidinylpropyl ester are produced.

When the procedures of Example XLI are employed, using the appropriate2-alkoxycarbinol, 2-alkoxyalkanol, '2-aryloxycarbinol or2-aryloxyalkanol in place of the 2- dimethylaminoethanol of Part B ofExample XLI together with the product of Part A of Example XLI, the4-(6,7- dimethoxyquinazolin-4-yl)-piperazine 1 carboxylic acid,2-methyl-2-propoxypropyl ester, the 2-methyl-2-isobutoxypropyl ester,the 2-methyl-2-phenoxypropyl ester, the 2- methyI-Z-naphthoxypropylesters, the 2-methyl-2-xyloylpropyl ester and theZ-methyI-Z-methoxypropyl ester may be formed.

Example XLIII Five parts, by weight of 4-(6,7-dimethoxyquinazolin-4-yl)-piperaZine-1- carboxylic acid, 2-methyl-2-aminopropy1 ester,prepared by the method of Example XLI, is dis solved in pyridine. To thesolution is added, dropwise, at 0 C., a slight excess of propionylchloride. After the addition is complete, the resultant mixture isheated at reflux. The cooled mixture is diluted with water and theproduct 4-(6,7-dimethoxyquinazolin 4 yl)-piperazine-lcarboxylic acid,2-methyl-2-ethamidopropyl ester is removed by filtration or extractionof the aqueous solution with methylene chloride.

In a similar manner, the 2-methyl-2-formamidopropyl ester and the 2methyI-Z-butyramidopropyl ester are formed.

A R; R R1: J

031110 CH3 CH3 CH3 OH Isobutoxy O H H H NHg OH 01130 CzHa H (I) ExamplesXLVI.Preparation of4-(6,7-dimethyoxyquinolin-4-yl)-piperazine-l-carboxylic acid, isobutylester A mixture of 3.4 g. (0.0152 mole) of4-chloro-6,7-dimethoxyquinoline, prepared by the general methods givenby B. Regel et al., J. Am. Chem. Soc., 68, 1264 (1964), and 5.65 g.(0.031 mole) of piperazine-l-carboxylic acid, isobutyl ester in 80 m1.of ethanol was heated at 130 C. for 2 hours. The resulting solution wasconcentrated to dryness and the residue slurried in water and filteredto separate 6.1 g. of crude product. Recrystallization from 50 ml. ofethanol afforded 4.3 g. (76%) of an otf-white crystalline product, M.P.172-173 C.

Analysis-Calcd. for C H O N (percent): C, 64.32; H, 7.29; N, 11.25.Found (percent): C, 64.13; H, 7.16; N, 11.36.

Example XLVIL-Preparation 4 (6,7 dimethoxyquinolin 4yl)-piperazine-1-carboxylic acid, 2-methyl-2- hydroxypropyl ester.

The methods used in Example XXXIX were used to prepare the2-methyl-2-hydroxypropyl ester Which evidenced a melting point of 172173C. and was recrystallized from ethyl acetate.

Example XLVIII The methods of Examples XXXVI, XXXVII, XXXVIII, XXXIX,XL, XLI, XLII, XLIII, XLVI, and XLVII are used to prepare compounds ofthe following formulae:

XXXVIII XXXIX, XL, XLI, XLII, XLIII, XLVI and XLVII are used to preparecompounds of the following formula:

N cmo- CHQO 5 1: Rn u I OH; H CH H H C2115 H H 02H; OH Isobutyl H H H BrCH OH; 02115 H Cl OH; H Isobutyl H NH; CHzOH H H Isobutyl H CH; IsobutylH CHQOH H CH; CaH1 H H fl) (3H OC(]3H H H H H a) H CH: H H (H) 11 H H H01117 H I OC (CH2)r-' H CH I O-CCH2 l 2)1- (32 5 H --O-CH u H H H H -NC-l? H H CH H -NC l l OH; H H H -NC- CHa UH; 11 CH; CH; II N CH H C2H5 H H--N\ /CzH5 /CH CH;

e 13 R14 R15 1 R5 R13 R14 R15 J H H H H H -'1\[I H H I-t l[ N H l I H HH H -N CH3 1O CH H 1'v CH3 H H H I I CaH7 15 052 H H H CH 9 S H H H H N"0 H H H H -I I- CH3 H H OH; H N ((3H,

C2H5 0H, Example L.Preparation of 4-(6,7-dimethoxyisoquinolin- H H H CH3(6H2): 1 yl) piperazine 1 carboxylic acid, isobutyl ester CH:

Part A: Preparation of N-carbethoxyhomoveratrylamine.To a solution of362 g. (2.0 moles) of homo- H H CH; H NCH veratrylamine in 500 ml. drybenzene was added a solution of 109 g. (1.0 mole) of ethyl chloroformatein 200 ml. of benzene, dropwise, keeping the temperature at H CH3 CH3 5O.. CH3 50-55 C. The resulting slurry was stirred for 16 hours at roomtemperature and poured into 500 ml. of water. The H H H CH3 -0C2H5benzene layer was separated, washed with 500 ml. of saturated sodiumbicarbonate solution and dried over E 40 sodium sulfate. Evaporation ofsolvent and distillation of H H 11 .0. 0 the residual oil aiforded 186g. (74%) of clear colorless 5 liquid; B.P. 174177 C. (0.2 mm), whichcrystallized on standing to give the product as a white crystallinesolid, M.P. 61-62 C. 3 H H H Part B: Preparation of 6,7dimethoxy-3,4-dihydro- 1(2H)-isoquinolinone.To one liter of stirredpolyphosphoric acid was added 330 g. (1.3 moles) of N-carbeth- H CHaCZHB H O- oxyhomoveratrylamine. The resulting mixture was stirred at 140C. for 30 minutes and poured onto 2 liters of icewater. The aqueoussolution was made basic with ammonium hydroxide and extracted severaltimes with chloroform. The combined extracts were dried over sodiumsulfate and evaporated to dryness. The residue was re H H H Hcrystallized from methylene chloride-ethyl acetate to afford 120 g.(44.5%) of white plates, M.P. 159-161" C. (53111 Part C: Preparation of6,7 dimethoxy-1(2H)-isoquin0linol1e.A mixture of 46.0 g. (0.222 mole) of6,7- I dimethoxy-3,4-dihydro-1(2H)-isoquinolinone and 7.0 g. of V 25%palladium on carbon was stirred at 240 C. for 30 n H H N "('H3 minutes(when hydrogen evolution had ceased) under a 0 6O nitrogen atmosphere.The mixture was cooled to room I} temperature and leached several timeswith hot chloro- H H H H Y form. The combined chloroform extracts wereconcen- H trated to dryness to afford 39.0 g. (86%) of white crystallineproduct, M.P. 228-232 C. g (7H3 Part D: Preparation of 1chloro-6,7-dimethoxyiso- H CH3 H H NOCH quinoline.A mixture containing39 g. (0.191 mole) of 5 6,7-dimethoXy-1 (2H)-isoquinolinone' and 200 ml.of phosphorous oxychloride was stirred at reflux for 1 hour. The H H Hresulting amber solution was concentrated to dryness and H the residuedissolved in methylene chloride and added slowly to 100 ml. ofconcentrated ammonium hydroxide H H H solution. The methylene chloridelayer was separated and the aqueous layer extracted with three 100 ml.portions of methylene chloride. The combined organic extracts were driedover sodium sulfate and evaporated to afiord 35.0

39 g. (82%) of white crystalline product, M.P. 135l37 C.

Analysis.-Calcd. for C H NO Cl (percent): C, 59.07; H, 4.51; N, 6.26;Cl, 15.85. Found (percent): C, 59.33; H, 4.60; N, 6.30; Cl, 16.06.

Part B: Preparation of 4-(6,7-dimethoxyisoquinolin-1-yl)-piperazine-1-carboxylic acid, isobutyl ester.A mixture containing4.0 g. (0.018 mole) of 1-chloro-6,7-dimethoxy-isoquinoline and 6.7 g.(0.036 mole) of piperazine-l-carboxylic acid, isobutyl ester in 80 ml.of ethanol was heated at 130 C. for 16 hours in a closed vessel. Theresulting amber solution was concentrated, slurried in water andfiltered to give 4.3 g. of crude product. This was recrystallized from30 ml. of methanol to afford 2.58 g. (38.5%) of product as slightly pinkneedles, M.P. 130- 132 C.

AnaIysis.Calcd. for C H N O (percent): C, 64.32; H, 7.29; N, 11.25.Found (percent): C, 64.47; H, 7.16; N, 11.29.

Example LI.-Preparation of 4 (6,7dimethoxyisoquinolin-l-yl)-piperazine-1-carboxylic acid esters The1-chloro-6,7-dimethoxyisoquinoline, produced by the methods of Part D ofExample L was reacted with the appropriate piperazine-l-carboxylic acidester, according to the methods of Part E of Example L to yield thefollowing compounds: 4 (6,7-dimethoxyisoquinolin-1-yl)-piperazine-l-carboxylic acid, ethyl ester; M.P. 130131 C.;recrystallized from isopropyl ether; M.P. of hydrochloride salt 107108C. (decomposition).

The methods of Example XXXIX were used to prepare the followingcompound: 4-(6,7-dimethoxyisoquinolin-1- yl)-piperazine-1-carboxylicacid, 2 methyl-Z-hydroxypropyl ester; M.P. 133-134" C.; recrystallizedfrom ethyl acetate-hexane; M.P. of hydrochloride salt 110 C.(decomposition).

Example LII.Preparation of 1-ethylamino-6,7- dimethoxyisoquinoline The1-chloro-6,7-dimethoxyisoquinoline, produced by the methods of Part D ofExample L, was reacted with ethylamine, according to the methods of PartE of Example L, to yield 1-ethylamino-6,7-dimethoxyisoquinoline, whichevidenced a melting point of 194195 C. and was recrystallized frommethanol-water. The hydrochloride salt evidenced a melting point of224-225" C. (decomposition).

Example LIII.-Preparation of l-piperazinyl- 6,7-dimethoxyisoquinoline Asolution of 84.0 g. (0.243 mole) of4-(6,7-dimethoxyisoquinolin-l-yl)-piperazine-1-carboxylic acid, ethylester, prepared by the methods of Example LI, in one liter of methanoland 250 ml. of 30% sodium hydroxide solution was refluxed for 18 hours.The resulting suspension was concentrated to remove the methanol,diluted with 500 ml. of water and extracted with three 250 ml. portionsof methylene chloride. The combined extracts were dried over sodiumsulfate and concentrated to 250 ml. To this was added 700 ml. ofisopropyl ether and the solution concentrated to 300 ml., chilled in anice bath and filtered to separate 51 g. (77%) of white crystallineproduct M.P. 134-1355 C. An additional 15 g. (22.6%) of material wasobtained by further concentration of the mother liquor.

Example LIV.Preparation of 4 (6,7dimethoxyisoquinolin-l-yl)-piperazine-1-carboxylic acid,Z-dimethylaminoethyl ester Part A: Preparation of4-(6,7-dimethoxyisoquinolin-lyl)-piperazine-l-thiol carboxylic acid,phenyl ester.-To a cold C.) solution of 19.0 (0.0695 mole) ofl-piperazinyl-6,7-dimethoxyisoquinoline, prepared by the methods ofExample LII-I, and 7.65 g. (0.076 mole) of triethylamine in 100 ml. ofmethylene chloride was added, dropwise, 12.0 g. (0.0695 mole) of phenylchlorothiolformate. The resulting suspension was allowed to stir at roomtemperature for 15 minutes and diluted with .ml. of methylene chloride.This solution was washed with two 50 ml. portions of water, dried oversodium sulfate and concentrated to a crystalline residue. The residuewas recrystallized from 100 ml. of methanol to separate 18.7 g. (66%) ofproduct as a pale yellow crystalline solid, M.P. 137-138 C.

Part B: Preparation of 4-('6,7-dimethoxyisoquinolin-1- yl)-piperazine-1-carboxylic acid, Z-dimethylaminoethyl ester.To asuspension of 1.6 g. (0.044 mole) of sodium hydride (60% mineral oildispersion) in 100 ml. of tetrahydrofuran was added 3.92 g. (0.44 mole)of Z-dimethylaminoethanol and the solution refluxed until gas evolutionceased (45 minutes). After cooling to room temperature 4.1 g. (0.01mole) of 4-(6,7-dimethoxyisoquinolin- 1-yl)-piperazine-l-thiolcarboxylicacid, phenyl ester was added and the solution stirred at roomtemperature for 30 minutes. This was diluted with 70 ml. of water andconcentrated to remove the tetrahydrofuran, and the resulting solutionextracted with three 100 ml. portions of methylene chloride. Thecombined extracts were dried over sodium sulfate and evaporated to leavea viscous oil which was triturated with isopropyl ether to separate 3.1g. (80%) of white crystalline product M.P. 114-115" C. Recrystallizationfrom methylene chloride-isopropyl ether mixture gave 2.3 g. of whitecrystalline product, M.P. 115 C.

Example LV M.P. hy- M.P. droehlobase, C. ride, C.

Recrystallization solvent.

Methanol. Purified by chroma- Ra R1 OH(OH) 3 3 2 H CH to a h CH2CH3 gr py CHZCHQ Acetone-water.

M.P. hy- M.P. drochlobase, 0. ride, 0.

Recrystallization solvent Ethyl acetate. Methanol.

ll -NCCII 137-138 1 157-8 Methylene chlloridoisopropyl other.

H NOOHZOH3 146-147 -7 Methylene chlorideisopropyl ether.

